CN1889955A

CN1889955A - Tricyclic imidazopyridines for use as gastric secretion inhibitors

Info

Publication number: CN1889955A
Application number: CNA2004800368766A
Authority: CN
Inventors: W·布尔; M·V·基萨; P·J·齐默曼; C·布雷姆; W·-A·西蒙; W·克罗默; S·波斯蒂乌斯; A·帕尔默
Original assignee: AUSTANA PHARMACEUTICAL GmbH
Current assignee: AUSTANA PHARMACEUTICAL GmbH; Takeda GmbH
Priority date: 2003-12-19
Filing date: 2004-12-17
Publication date: 2007-01-03
Also published as: CA2549030A1; AU2004298788A1; KR20070007041A; TW200526212A; IL175724A0; EA200601106A1; EP1696921A1; JP2007514714A; WO2005058325A8; AR046941A1; NO20063220L; WO2005058325A1; BRPI0417263A; ZA200604134B; US20070066674A1

Abstract

The invention provides compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.

Description

Tricyclic imidazopyridines as gastric secretion inhibitors

Invention field

The present invention relates to the enantiomer of tricyclic imidazopyridines, the preparation method of these enantiomer and the application that in pharmaceuticals industry, is used to prepare medicine thereof as reactive compound.

Prior art

U.S. patent 4,468, and 400 have described tricyclic antidepressants imidazo [1, the 2] pyridine compounds that has with the condensed different ring systems of imidazopyridine precursor structure, and described chemical compound is applicable to treatment peptic ulcer disease.International Patent Application WO 95/27714, WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/63211, WO 01/72756, WO01/72754, WO 01/72755, WO 01/72757, WO 02/34749, WO03/014120, WO 03/016310, WO 03/014123, WO 03/068774 and WO03/091253 disclose the tricyclic imidazopyridines with specific substitute mode, according to wherein describing, described chemical compound is suitable for treating disorder of gastrointestinal tract equally.

The description of invention

Have been found that now the chemical compound of describing as racemic mixture can be separated into their enantiomer, perhaps can prepare enantiomer by Stereoselective method in WO 03/014123 for example.Find beyond expectationly that also compare with its optical antipode shown in the formula 2, the enantiomer of formula 1 has the excretory activity of significant gastric acid inhibitory.

Though the tricyclic antidepressants imidazo of enantiomer-pure [1,2-a] pyridine derivate is known, for example is recorded in the International Patent Application WO 95/27714, to compare with formula 2 chemical compounds, formula 1 chemical compound has more that high activity is unforeseeable.Up to now, for any combination of substituent R 1, R2, R3 and Arom, has the excretory activity of more significant gastric acid inhibitory and the enantiomer of preferred formula 1 was not described as yet because compare with its optical antimer shown in the formula 2.

Therefore, the invention provides formula 1 chemical compound:

Wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxyl-1-4C-alkyl or 1-4C-alkoxy carbonyl;

R2 is hydrogen, 1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, hydroxyl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy carbonyl;

R3 is hydroxyl-1-2C-alkyl, 1-4C-alkoxyl-1-2C-alkyl, 1-4C-alkoxyl-1-4C-alkoxyl-1-2C-alkyl, 1-4-C-alkoxy carbonyl or group-CO-NR31R32,

Wherein

R31 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl, and

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl, perhaps wherein

R31 is pyrrolidino, piperidino, morpholino with R32 with the nitrogen-atoms that they were connected,

Arom is selected from following monocycle or aryl bicyclic by what R4, R5, R6 and R7 replaced: phenyl, naphthyl, pyrrole radicals, pyrazolyl, imidazole radicals, 1,2,3-triazolyl, indyl, benzimidazolyl, furyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, different  azoles base, pyridine radicals, pyrimidine radicals, quinolyl and isoquinolyl

R4 is hydrogen, 1-4C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl, carboxyl, 1-4C-alkoxy carbonyl, carboxyl-1-4C-alkyl, 1-4C-alkoxy carbonyl-1-4C-alkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy group, aryl-1-4C-alkoxyl, trifluoromethyl, nitro, amino, one or two-1-4C-alkyl amino, 1-4C-alkyl-carbonyl-amino, 1-4C-alkoxycarbonyl amino, 1-4C-alkoxyl-1-4C-alkoxycarbonyl amino or sulfonyl

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl or hydroxyl,

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

Wherein

Aryl is the phenyl of phenyl or replacement, the phenyl of described replacement has 1,2 or 3 and identical or different is selected from following substituent group: 1-4C-alkyl, 1-4C-alkoxyl, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group, and the salt of these chemical compounds.

The 1-4C-alkyl is meant the straight or branched alkyl with 1-4 carbon atom.The example that can mention has butyl, isobutyl group, sec-butyl, the tert-butyl group, propyl group, isopropyl, ethyl and methyl.

The 3-7C-cycloalkyl is meant cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl, and wherein cyclopropyl, cyclobutyl and cyclopenta are preferred.

The 1-4C-alkoxyl is meant the group that also comprises the straight or branched alkyl with 1-4 carbon atom except oxygen atom.The example that can mention has butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxyl group, isopropoxy, and preferred ethyoxyl and methoxyl group.

1-4C-alkoxyl-1-4C-alkyl is meant an above-mentioned 1-4C-alkyl that is replaced by 1 above-mentioned 1-4C-alkoxyl.The example that can mention has methoxy, methoxy ethyl and butoxyethyl group.

1-4C-alkoxy carbonyl (CO-1-4C-alkoxyl) is meant the carbonyl that has connected 1 above-mentioned 1-4C-alkoxyl on it.The example that can mention has methoxycarbonyl (CH ₃O-C (O)-) and ethoxy carbonyl (CH ₃CH ₂O-C (O)-).

For the object of the invention, halogen is bromine, chlorine and fluorine.

The 2-4C-alkenyl is meant the straight or branched alkenyl with 2-4 carbon atom.The example that can mention has crotyl, 3-cyclobutenyl, 1-acrylic and 2-acrylic (pi-allyl).

The 2-4C-alkynyl is meant the straight or branched alkynyl with 2-4 carbon atom.The example that can mention has 2-butyne base, 3-butynyl, 2-propynyl (propargyl) and preferred 1-acetenyl, 1-propinyl and ethyl acetylene base.

Hydroxyl-1-4C-alkyl is meant the above-mentioned 1-4C-alkyl that is replaced by hydroxyl.The example that can mention has hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl.

The 1-2C-alkyl is meant methyl or ethyl.

Hydroxyl-1-2C-alkyl is meant the above-mentioned 1-2C-alkyl that is replaced by hydroxyl.The example that can mention has hydroxymethyl and 2-hydroxyethyl.

1-4C-alkoxyl-1-2C-alkyl is meant an above-mentioned 1-2C-alkyl that is replaced by an above-mentioned 1-4C-alkoxyl.The example that can mention has methoxy, methoxy ethyl and butoxyethyl group.

1-4C-alkoxyl-1-4C-alkoxyl is meant an above-mentioned 1-4C-alkoxyl that is replaced by another 1-4C-alkoxyl.The example that can mention has 2-(methoxyl group) ethyoxyl (CH ₃-O-CH ₂-CH ₂-O-) and 2-(ethyoxyl) ethyoxyl (CH ₃-CH ₂-O-CH ₂-CH ₂-O-).

1-4C-alkoxyl-1-4C-alkoxyl-1-2C-alkyl is meant an above-mentioned 1-4C-alkoxyl that is replaced by a 1-4C-alkoxyl-1-2C-alkyl.Its example that can mention has 2-(methoxyl group) ethoxyl methyl (CH ₃-O-CH ₂-CH ₂-O-CH ₂-).

The 1-7C-alkyl is meant the straight or branched alkyl with 1-7 carbon atom.The example that can mention has heptyl, different heptyl (5-methyl hexyl), hexyl, isohesyl (4-methyl amyl), new hexyl (3, the 3-dimethylbutyl), amyl group, neopentyl-(3-methyl butyl), neopentyl-(2, the 2-dimethyl propyl), butyl, isobutyl group, sec-butyl, the tert-butyl group, propyl group, isopropyl, ethyl and methyl.

Carboxyl-1-4C-alkyl is meant for example carboxyl methyl (CH ₂COOH) or carboxy ethyl (CH ₂CH ₂COOH).

1-4C-alkoxy carbonyl-1-4C-alkyl is meant an above-mentioned 1-4C-alkyl that is replaced by an above-mentioned 1-4C-alkoxy carbonyl.The example that can mention has ethoxy carbonyl methyl (CH ₃CH ₂OC (O) CH ₂-).

Aryl-1-4C-alkyl is meant the 1-4C-alkyl that is replaced by aryl.The example that can mention has benzyl.

Aryl-1-4C-alkoxyl is meant the 1-4C-alkoxyl that is replaced by aryl.The example that can mention has benzyloxy.

Except nitrogen-atoms, one or two-1-4C-alkyl amino contain one or two above-mentioned 1-4C-alkyl.Preferred two-1-4C-alkyl amino and particularly dimethylamino, diethylamino or diisopropylaminoethyl.

The 1-4C-alkyl-carbonyl-amino is meant the amino that is connecting the 1-4C-alkyl-carbonyl on it.The example that can mention has propiono amino (C ₃H ₇C (O) NH-) and acetyl-amino (acetylamino, CH ₃C (O) NH-).

The 1-4C-alkoxycarbonyl amino is meant the amino that is replaced by above-mentioned 1-4C-alkoxy carbonyl.The example that can mention has the amino and methoxycarbonyl amino of ethoxy carbonyl.

1-4C-alkoxyl-1-4C-alkoxy carbonyl is meant the carbonyl that is replaced by above-mentioned 1-4C-alkoxyl-1-4C-alkoxyl.The example that can mention has 2-(methoxyl group) ethoxy carbonyl (CH ₃-O-CH ₂CH ₂-O-CO-) and 2-(ethyoxyl) ethoxy carbonyl (CH ₃CH ₂-O-CH ₂CH ₂-O-CO-).

1-4C-alkoxyl-1-4C-alkoxycarbonyl amino is meant the amino that is replaced by above-mentioned 1-4C-alkoxyl-1-4C-alkoxy carbonyl.The example that can mention has amino and 2-(ethyoxyl) the ethoxy carbonyl amino of 2-(methoxyl group) ethoxy carbonyl.

The group Arom that can mention has for example following substituent group: 4-acetoxyl group phenyl, the 4-acetylamino phenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, the 4-methoxyphenyl, 3-benzyloxy phenyl, 4-benzyloxy phenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,5-two (trifluoromethyl) phenyl, the 4-butoxy phenyl, the 2-chlorphenyl, the 3-chlorphenyl, the 4-chlorphenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-5-nitrobenzophenone, 4-chloro-3-nitrobenzophenone, 3-(4-chlorophenoxy) phenyl, 2, the 4-Dichlorobenzene base, 3, the 4-difluorophenyl, 2, the 4-dihydroxy phenyl, 2, the 6-Dimethoxyphenyl, 3,4-dimethoxy-5-hydroxy phenyl, 2, the 5-3,5-dimethylphenyl, 3-ethyoxyl-4-hydroxy phenyl, the 2-fluorophenyl, the 4-fluorophenyl, the 4-hydroxy phenyl, 2-hydroxyl-5-nitrobenzophenone, 3-methoxyl group-2-nitrobenzophenone, the 3-nitrobenzophenone, 2,3, the 5-trichlorophenyl, 2,4,6-trihydroxy phenyl, 2,3, the 4-trimethoxyphenyl, 2-hydroxyl-1-naphthyl, 2-methoxyl group-1-naphthyl, 4-methoxyl group-1-naphthyl, 1-methyl-2-pyrrole radicals, the 2-pyrrole radicals, 3-methyl-2-pyrrole radicals, 3,4-dimethyl-2-pyrrole radicals, 4-(2-methoxycarbonyl ethyl)-3-methyl-2-pyrrole radicals, 5-ethoxy carbonyl-2,4-dimethyl-3-pyrrole radicals, 3,4-two bromo-5-methyl-2-pyrrole radicals, 2,5-dimethyl-1-phenyl-3-pyrrole radicals, 5-carboxyl-3-ethyl-4-methyl-2-pyrrole radicals, 3,5-dimethyl-2-pyrrole radicals, 2,5-dimethyl-1-(4-trifluoromethyl)-3-pyrrole radicals, 1-(2,6-dichlor-4-trifluoromethyl phenyl)-the 2-pyrrole radicals, 1-(2-nitrobenzyl)-2-pyrrole radicals, 1-(2-fluorophenyl)-2-pyrrole radicals, 1-(4-Trifluoromethoxyphen-l)-2-pyrrole radicals, 1-(2-nitrobenzyl)-2-pyrrole radicals, 1-(4-ethoxy carbonyl)-2,5-dimethyl-3-pyrrole radicals, 5-chloro-1,3-dimethyl-4-pyrazolyl, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl, 1-(4-benzyl chloride base)-5-pyrazolyl, 1,3-dimethyl-5-(4-chlorophenoxy)-4-pyrazolyl, 1-methyl-3-trifluoromethyl-5-(3-4-trifluoromethylphenopendant)-4-pyrazolyl, 4-methoxycarbonyl-1-(2, the 6-Dichlorobenzene base)-the 5-pyrazolyl, 5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3,5-dimethyl-1-phenyl-4-imidazole radicals, 4-bromo-1-methyl-5-imidazole radicals, 2-1-Butyl-1H-imidazole base, 1-phenyl-1,2,3-triazole-4-base, the 3-indyl, the 4-indyl, the 7-indyl, 5-methoxyl group-3-indyl, 5-benzyloxy-3-indyl, 1-benzyl-3-indyl, 2-(4-chlorphenyl)-3-indyl, 7-benzyloxy-3-indyl, 6-benzyloxy-3-indyl, 2-methyl-5-nitro-3-indyl, 4,5,6,7-tetrafluoro-3-indyl, 1-(3, the 5-difluorobenzyl)-the 3-indyl, 1-methyl-2-(4-trifluoromethoxy phenoxy base)-3-indyl, 1-methyl-2-benzimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, the 2-furyl, the 3-furyl, 5-(2-nitro-4-trifluoromethyl)-2-furyl, 4-ethoxy carbonyl-5-methyl-2-furyl, 5-(2-Trifluoromethoxyphen-l)-2-furyl, 5-(4-methoxyl group-2-nitrobenzophenone)-2-furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo group-2-furyl, the 2-benzofuranyl, the 2-thienyl, the 3-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl, 5-(4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3-phenoxy group-2-thienyl, 5-carboxyl-2-thienyl, 2,5-two chloro-3-thienyls, 3-methoxyl group-2-thienyl, the 2-benzothienyl, 3-methyl-2-benzothienyl, 2-bromo-5-chloro-3-benzothienyl, the 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2,4-two chloro-5-thiazolyls, 2-diethylamino-5-thiazolyl, 3-methyl-different  the azoles of 4-nitro-5-base, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, 6-methyl-2-pyridine radicals, 3-hydroxyl-5-hydroxymethyl-2-methyl-4-pyridine radicals, 2,6-two chloro-4-pyridine radicals, 3-chloro-5-trifluoromethyl-2-pyridine radicals, 4,6-dimethyl-2-pyridine radicals, 4-(4-chlorphenyl)-3-pyridine radicals, 2-chloro-5-methoxyl group-carbonyl-6-methyl-4-phenyl-3-pyridine radicals, 2-chloro-3-pyridine radicals, 6-(3-4-trifluoromethylphenopendant)-3-pyridine radicals, 2-(4-chlorophenoxy)-3-pyridine radicals, 2,4-dimethoxy-5-pyrimidine radicals, the 2-quinolyl, the 3-quinolyl, the 4-quinolyl, 2-chloro-3-quinolyl, 2-chloro-6-methoxyl group-3-quinolyl, 8-hydroxyl-2-quinolyl and 4-isoquinolyl.

The suitable salt of formula 1 chemical compound (this depends on replacement) is all acid-addition salts particularly.May be particularly mentioned the pharmacology and go up inorganic and organic acid officinal salt commonly used.What be fit to is and formed water solublity of following acid and water-insoluble acid-addition salts: hydrochloric acid; hydrobromic acid; phosphoric acid; nitric acid; sulphuric acid; acetic acid; citric acid; the D-gluconic acid; benzoic acid; 2-(4-hydroxy benzoyl) benzoic acid; butanoic acid; sulfosalicylic acid; maleic acid; lauric acid; malic acid; fumaric acid; succinic acid; oxalic acid; tartaric acid; pounce on acid; stearic acid; toluenesulfonic acid; methanesulfonic acid or 3-hydroxyl-2-naphthoic acid; wherein described acid is used for the preparation of salt to wait molar ratio or different ratios, this depends on that used acid is monoacid or polyprotic acid and required salt.

Can pass through method known to those skilled in the art, unacceptable salt changes officinal salt on the pharmacology who obtains as industrial products at first in the The compounds of this invention with for example preparing in commercial scale.

Those skilled in the art are clear, obtain if The compounds of this invention and salt thereof for example separate with crystal habit, and then it can contain the solvent of various amounts.Therefore the present invention also comprises various solvates, especially all hydrates of formula 1 chemical compound, and comprises all solvates, especially all hydrates of the salt of formula 1 chemical compound.

Particularly, the present invention relates to formula of the present invention 1 chemical compound and/or its salt of the formula that is substantially free of 2 chemical compounds and/or its salt.

In the context of the invention, being substantially free of is expression, and formula 1 chemical compound and/or its salt contain formula 2 chemical compounds and/or its salt less than 10% weight.Preferably, " being substantially free of " is expression, and formula 1 chemical compound and/or its salt contain formula 2 chemical compounds and/or its salt less than 5% weight.In the most preferred embodiment, " being substantially free of " is expression, and formula 1 chemical compound and/or its salt contain formula 2 chemical compounds and/or its salt less than 2% weight.

The chemical compound that can mention is formula 1 chemical compound that is defined as follows, wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is 1-4C-alkyl, halogen, hydroxyl-1-4C-alkyl, 2-4C-alkenyl or 3-7C-cycloalkyl,

Wherein

R31 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl,

And

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl,

Perhaps wherein

R31 and R32 with the nitrogen-atoms that they were connected be pyrrolidino, piperidino,

Morpholino,

Arom is selected from following monocycle or aryl bicyclic by what R4, R5, R6 and R7 replaced:

Phenyl, naphthyl, pyrrole radicals, pyrazolyl, imidazole radicals, 1,2,3-triazolyl, indyl, benzimidazolyl, furyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, different  azoles base, pyridine radicals, pyrimidine radicals, quinolyl and isoquinolyl

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

Wherein

Also the chemical compound that can mention is formula 1 chemical compound that is defined as follows, wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl,

And

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl,

Perhaps wherein

Morpholino,

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

Wherein

May be particularly mentioned formula 1 chemical compound that is defined as follows, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen, hydroxyl-1-4C-alkyl or 2-4C-alkenyl,

R3 is hydroxyl-1-2C-alkyl, 1-4C-alkoxyl-1-2C-alkyl, 1-4C-alkoxyl-1-4C-alkoxyl-1-2C-alkyl or group-CO-NR31R32,

Wherein

R31 is hydrogen, 1-7C-alkyl,

R32 is hydrogen, 1-7C-alkyl,

Perhaps wherein

Phenyl, furyl, thienyl, pyrrole radicals or pyridine radicals that Arom is replaced by R4 and R5,

Wherein

R4 is hydrogen, 1-4C-alkyl, hydroxyl-1-4C-alkyl, 1-4C-alkoxyl, halogen or hydroxyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl, halogen or hydroxyl, and the salt of these chemical compounds.

Also may be particularly mentioned formula 1 chemical compound that is defined as follows, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen, hydroxyl-1-4C-alkyl or 2-4C-alkenyl,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

Phenyl, furyl, thienyl or pyridine radicals that Arom is replaced by R4 and R5,

Wherein

Formula 1 chemical compound that is defined as follows provides emphatically, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen, hydroxyl-1-4C-alkyl or 2-4C-alkenyl,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

Wherein

Formula 1 chemical compound that is defined as follows also provides emphatically, wherein

R1 is the 1-4C-alkyl,

R2 is the 1-4C-alkyl,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

Phenyl, furyl, thienyl or pyridine radicals that Arom is replaced by R4 and R5,

Wherein

R1 is the 1-4C-alkyl,

R2 is halogen, hydroxyl-1-4C-alkyl or 2-4C-alkenyl,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

Phenyl, furyl, thienyl or pyridine radicals that Arom is replaced by R4 and R5,

Wherein

Formula 1 chemical compound that is defined as follows stresses and provides, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen or hydroxyl-1-4C-alkyl,

R3 is 1-4C-alkoxyl-1-2C-alkyl or group-CO-NR31R32, wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 is pyrrolidino with R32 with the nitrogen-atoms that they were connected,

Phenyl or thienyl that Arom is replaced by R4,

Wherein

R4 is hydrogen, 1-4C-alkyl or halogen, and the salt of these chemical compounds.

Formula 1 chemical compound that is defined as follows also stresses and provides, wherein

R1 is the 1-4C-alkyl,

R2 is the 1-4C-alkyl,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Arom is a phenyl,

And the salt of these chemical compounds.

As particularly preferred example, following exemplary formula 1 chemical compound can according to hereinafter more the conventional method of depicted in greater detail synthesize:

R1	R2	R3	Arom
R1	R2	R3	Arom	CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	Phenyl
CH ₃	-CH ₂OH	-C(O)-N(CH ₃) ₂	Phenyl	CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	Phenyl
CH ₃	-CH ₂OH	-C(O)-N(CH ₃) ₂	Phenyl	CH ₃	Br	-C(O)-N(CH ₃) ₂	Phenyl
CH ₃	-CH ₂CH ₃	-C(O)-N(CH ₃) ₂	Phenyl	CH ₃	Br	-C(O)-N(CH ₃) ₂	Phenyl
CH ₃	-CH ₂CH ₃	-C(O)-N(CH ₃) ₂	Phenyl	CH ₃	CH ₃	-C (O)-pyrrolidino	Phenyl
CH ₃	CH ₃	-C(O)-N(H)CH ₃	Phenyl	CH ₃	CH ₃	-C (O)-pyrrolidino	Phenyl
CH ₃	CH ₃	-C(O)-N(H)CH ₃	Phenyl	CH ₃	CH ₃	-C(O)-NH ₂	Phenyl
CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	The 2-aminomethyl phenyl	CH ₃	CH ₃	-C(O)-NH ₂	Phenyl
CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	The 2-aminomethyl phenyl	CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	The 2-fluorophenyl
CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	The 4-fluorophenyl	CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	The 2-fluorophenyl
CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	The 4-fluorophenyl	CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	Thiophene-2-base
CH ₃	CH ₃	CH ₂OCH ₃	Phenyl	CH ₃	CH ₃	-C(O)-N(CH ₃) ₂	Thiophene-2-base

Other formula 1 chemical compound of not mentioning as an example can make according to similar approach well known by persons skilled in the art.

The compounds of this invention can be made by corresponding racemic mixture by the following method: according to technology well known by persons skilled in the art, the optical antimer of required formula 1 chemical compound and formula 2 is separated.Separation can be for example realizes crystallization of non-mapping salt or the preparative chromatography by the use chiral column by coming after the racemic mixture of the free acid chemical compound of the free acid chemical compound of formula 1 and formula 2 and suitable optically pure acid are reacted.

For this purpose, the racemic mixture of formula 1 chemical compound and formula 2 chemical compounds, formula 1 chemical compound that preferred wherein R2 is the 1-4C-alkyl and the racemic mixture of formula 2 chemical compounds can make according to the method for for example describing in WO 03/014123 or by similar reactions steps (reaction scheme 1).1-aryl-3-(imidazo [1 of formula 4,2-a] pyridine-7-yl)-third-1-ketone is such to be made: with Eschenmoser ' s salt for example with the 8-hydroxyl imidazo [1 of formula 3,2-a] pyridine carry out amino methylization, then with suitable for example 1-(1-aryl-ethylene base)-pyrrolidine reaction of enamine compound.The racemic mixture that the ketone of formula 4 transforms an accepted way of doing sth 1 chemical compound and formula 2 chemical compounds can adopt be similar to the method for describing among the WO 03/014123 finish (with for example sodium borohydride the carbonyl functional group is reduced, then for example sour as in the presence of the phosphoric acid with the glycol cyclization of gained formula 5).The racemic mixture that carries for example substituent formula 1 chemical compound of 6-acylamino-and formula 2 chemical compounds can be by method easily by the 7H-8 of formula 6,9-dihydropyran also [2,3-c]-imidazo [1,2-a] pyridine-6-carboxylate makes: with the cracking of ester functional group, for example come the cracking of ester functional group by carry out saponification with sodium hydroxide, obtained the carboxylic acid of corresponding formula 7, then with the carboxylic acid of formula 7 with suitable coupling reagent for example TBTU handle, add for example amine of coupling composition afterwards.

Reaction scheme 1

Perhaps, the racemic mixture of formula 1 chemical compound and formula 2 chemical compounds, preferred wherein R2 is that the formula 1 of hydrogen, halogen, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, hydroxyl-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy carbonyl and the racemic mixture of formula 2 chemical compounds can make by following reaction scheme 2,3 and 4.

Reaction scheme 2:

Replace by for example close electric aromatics, can directly formula 8 chemical compounds be transformed the racemic mixture of an accepted way of doing sth 1 chemical compound and formula 2 chemical compounds.

Perhaps; by for example Vilsmeier formylated; can at first formula 8 chemical compounds be transformed an accepted way of doing sth 9 chemical compounds; carrying out other derivative reaction well known by persons skilled in the art then (for example reduces aldehyde radical; carry out etherificate then if necessary; perhaps with aldehyde radical oxidation, esterification then), with the racemic mixture of production 1 chemical compound and formula 2 chemical compounds.

Another possible method of the racemic mixture of acquisition formula 1 chemical compound and formula 2 chemical compounds is for example carried out like this: form reaction as Heck coupling reaction, Suzuki coupling reaction or Sonogashira coupling reaction by C-C key for example, transform wherein formula 1 chemical compound of R2=halogen and the racemic mixture of formula 2 chemical compounds.If necessary, the product of these coupling reactions further can be modified, for example, by the CC multikey was also further modified originally.Wherein the racemic mixture of formula 1 chemical compound of R2=halogen and formula 2 chemical compounds can for example use the bromination reaction of bromide reagent such as N-bromine butanimide to make by formula 8 chemical compounds by for example halogenating reaction.

Formula 8 chemical compounds (R2=H)-or the racemic mixture of formula 1 chemical compound and formula 2 chemical compounds generally can for example make according to the reaction sequence of describing in the reaction scheme 3.

Reaction scheme 3

Formula 12 chemical compounds can for example be obtained by formula 3 chemical compounds by the following method: carry out the O-alkylation, allow the O-alkylate of formula 11 carry out thermoinducible Claisen-rearrangement reaction then.Adopt standard conditions; use suitable protecting group Prot for example valeryl or dimethyl-(1; 1; 2-trimethyl-propyl group)-siloxy protects the alcohol functional group in formula 12 chemical compounds; acquisition formula 13 chemical compounds; can be in next reactions steps, for example use the suitable Grubbs catalyst that is suitable for introducing the Arom residue to carry out for example cross substitution reaction.Can be with formula 14 product deprotections, and can use method known to those skilled in the art, for example use acid condition to carry out cyclization, generate the racemic mixture of required formula 8 chemical compounds or formula 1 chemical compound and formula 2 chemical compounds.

Formula 10 chemical compounds can for example make according to the illustrative methods of describing in the reaction scheme 4 according to being similar to the method for describing among the WO 03/014123.

Reaction scheme 4

By formula 15 compound formulas 16 chemical compounds is according to from carrying out as method known to those skilled in the art, for example carries out according to being similar to the reaction of describing by way of example in the International Patent Application WO 03/014123.With formula 16 hydrogenation of compounds accepted way of doing sth 10 chemical compounds is according to from as method known to those skilled in the art, uses the standard reaction condition, for example uses hydrogen/Pd (0) to carry out.

Perhaps, formula 1 chemical compound can be according to making by Stereoselective method as the reactions steps of describing in the reaction scheme 5.Formula 17 chemical compounds can make by formula 4 chemical compounds are carried out asymmetric reduction.The several different methods of carrying out the asymmetric reduction of prochiral ketones is known (referring to for example E.N.Jacobsen, A.Pfaltz, Y.Yamamoto, ComprehensiveAsymmetric Catalysis, Vol.l-lil, Springer, Berlin, 1999), comprise interior catalytic hydrogenation, catalytic transfer hydrogenation, chiral reduction agent (for example chirality borine), the achirality Reducing agent in the presence of chiral auxiliary or chiral catalyst, hydrosilylation (achirality silane and chiral catalyst are united use) and enzyme reduction.Use Noyori type chiral hydrogenation catalyst (RuCl ₂[PP] [NN]) asymmetric catalytic hydrogenation is the method for optimizing of glycol that is used for the enantiomer-pure of synthesis type 17.At general formula R uCl ₂Among [PP] [NN], PP is as the abbreviation of chirality diphosphine ligand, and NN is as the abbreviation of chiral diamine ligands.Can be about the instantiation of the detailed description of this method and hydrogenation catalyst referring to for example Angew.Chem.2001,113,40-75 and the document of wherein being quoted.Formula 17 derivants are transformed the 7H-8 of the enantiomer-pure of an accepted way of doing sth 1, and 9-dihydropyran also [2,3-c]-imidazo [1,2-a] pyridine can be by at SN ₂The method of carrying out under the condition is finished.For this purpose, the hydroxyl on the alpha-position of Arom group can be changed into suitable leaving group LG, for example by carrying out with carboxylic acid halides or sulfonic acid chloride esterification.For preparation formula 18a chemical compound, can be with phenolic hydroxyl group temporary protection.Suitable protecting group is described in for example T.W.Greene, P.G.M.Wuts " protecting group in the organic synthesis " the 3rd edition, J.Wiley﹠amp; Sons, New York is in 1999.Perhaps, for example can using, mentioned reagent changes into suitable leaving group LG, production 18b chemical compound with the phenolic hydroxyl group in formula 17 chemical compounds.Correlation technique is disclosed in the International Patent Application WO 95/27714.The chemical compound of the enantiomer-pure of formula 1 can be for example by with these intermediate 18a or 18b dipolar aprotic solvent for example the solution among DMF or the DMSO heat and make.The cyclization of formula 18b chemical compound can for example be carried out in the presence of alkali such as sodium hydride.Ground preferably, the cyclization of formula 17 glycol can for example use diisopropyl azodiformate and triphenylphosphine to finish under the Mitsunobu condition.

Reaction scheme 5

Formula 4 chemical compounds are known, for example are described among the WO 03/014123, and perhaps they can make (referring to for example reaction scheme 1) according to the known method that is similar to the preparation known compound.The purity of formula 4 chemical compounds has main influence for the reaction condition and the result of an asymmetric hydrogenation accepted way of doing sth 17 chemical compounds.Opposite with WO 03/014123, need further purification step, the crystallisation step in the presence of appropriate organic for example is as in an embodiment with as described in the exemplary approach.Formula 4 chemical compounds are changed into the proper method of other formula 4 chemical compounds that carry different substituents R3 shown in reaction scheme 6, and can illustrate: can be 7-(3-aryl-3-oxo-propyl group)-8-hydroxyl-imidazo [1 shown in the formula 19 of for example 1-4C-alkyl R33 wherein by following example, 2-a] pyridine-6-carboxylate transforms the acetal of an accepted way of doing sth 20, this can by for example in the presence of acid with 2, the 2-dimethoxy propane reacts realizes described conversion.With the cracking of ester functional group, for example come the cracking of ester functional group has been obtained the carboxylic acid of corresponding formula 21 by carry out saponification with sodium hydroxide, then with the carboxylic acid of formula 21 with for example TBTU processing of suitable coupling reagent, add for example amine of coupling composition afterwards, the derivant of production 22.Perhaps, can use lithium aluminium hydride for example that the ester of formula 20 is reduced into corresponding primary alconol, and hydroxyl can be activated, for example by for example using thionyl chloride or hydroxyl is changed into halogenide to mesyl chloride or sulphonic acid ester activates.Then can by use nucleophile for example the nucleophilic displacement reaction of alcoholates finish the mutual conversion of substituent R 3.At last, by for example in the presence of sour example hydrochloric acid with the acetal cracking of formula 22, come the ketone of acquisition formula 4.

Reaction scheme 6:

Described to be suitable for the synthetic another kind of method of formula 1 chemical compound in the reaction scheme 7.By formula 14 chemical compounds (referring to reaction scheme 3) being changed into chiral diol to two key hydrogenations.The chiral reagent that is suitable for this conversion is described in for example Aldrichimica Acta 1987,20 (1), among the 9-24.An example can mentioning is different loose pinanyl borine.Perhaps, achiral reagent and chiral catalyst can be united use.Described above formula 17 chemical compounds have been transformed an accepted way of doing sth 1 chemical compound.

Reaction scheme 7:

Equally, the optical antimer of formula 2 can use in the above and to describe and to make in the stereo selectivity mode in the method for reaction scheme 5 and 7 illustrated.For this purpose, must use the corresponding enantiomer of chiral catalyst/chiral reagent to transform respectively.

If necessary, carry out the derivatization (for example a radicals R 3 is changed into another radicals R 3 or a radicals R 2 is changed into another radicals R 2) of the chemical compound that obtains according to above-mentioned reaction scheme 1-7 equally in the manner known to persons skilled in the art.For example, wherein R2 and/or R3=-CO-1-4C-alkoxyl or the wherein chemical compound of R3=-CO-NR31R32 if desired, can carry out suitable derivatization (carbonylation of the metal catalytic of for example corresponding halogenated compound or change into amide with ester) in the manner known to persons skilled in the art, for example, in stage of formula 4,5,6,8 or 19 chemical compounds or preferably carry out derivatization, for example a kind of formula 1 chemical compound is changed into another kind of formula 1 chemical compound at more late time point.Provided instantiation in reaction scheme 1 (formula 6 chemical compounds being transformed the racemic mixture of an accepted way of doing sth 1 chemical compound and formula 2 chemical compounds) and the reaction scheme 6 (ketone of formula 19 being transformed the ketone of an accepted way of doing sth 4).

The invention still further relates to the method for synthesis type 1 chemical compound, described method comprises formula 8 chemical compounds that wherein R1, R3 and Arom are had the implication that provides at first

Transform the racemic mixture of its optical antimer shown in an accepted way of doing sth 1 chemical compound and the formula 2, wherein R1, R2, R3 and Arom have the implication that provides at first,

And

-its optical antimer shown in formula 1 chemical compound and the formula 2 separated and

-if necessary,, formula 1 chemical compound is carried out further derivatization in the racemic mixture stage of its optical antimer shown in formula 1 chemical compound and the formula 2 or after its optical antimer shown in formula 1 chemical compound and the formula 2 is separated.

The invention still further relates to the method for synthesis type 1 chemical compound, described method comprises that formula 13 chemical compounds that wherein R1, R2 and R3 are had an implication that provides at first change into formula 14 chemical compounds that wherein R1, R2, R3 and Arom have the implication that provides at first

And formula 14 chemical compounds are further transformed the racemic mixture of its optical antimer shown in an accepted way of doing sth 1 chemical compound and the formula 2

And

The invention still further relates to the method for synthesis type 1 chemical compound, described method comprises

-with formula 4 chemical compound asymmetric reductions with production 17 chemical compounds

Wherein R1, R2, R3 and Arom have the implication that provides at first,

-and with formula 17 a chemical compounds conversion accepted way of doing sth 1 compound or its salt.

-formula 14 chemical compounds are transformed an accepted way of doing sth 17 chemical compounds

Wherein R1, R2, R3 and Arom have the implication that provides at first,

The following example is in order to illustrate the present invention in more detail, rather than restriction the present invention.Unspecial other formula 1 chemical compound of describing its preparation can use conventional process technology equally, makes as mode well known by persons skilled in the art in a similar manner or certainly.Abbreviation ee represents enantiomeric excess, and RT represents retention time, and S/C represents the ratio of substrate and catalyst, and v represents volume.For the NMR signal, use following abbreviation: s (unimodal), d (bimodal), t (triplet), q (quartet), me (concentrated multiplet), b (wide).Use following unit: ml (milliliter), l (liter), nm (nanometer), mm (millimeter), mg (milligram), g (gram), mmol (mM), N (equivalent), M (mole), min (minute), MHz (] megahertz).

For specified chemical substance, also use following abbreviation:

(S)-BINAP (S)-2,2 '-two-(diphenylphosphino)-1,1 '-dinaphthalene

(R)-BINAP (R)-2,2 '-two-(diphenylphosphino)-1,1 '-dinaphthalene

(S)-and DAIPEN (2S)-(+)-1,1-two (4-methoxyphenyl)-3-methyl isophthalic acid, 2-butanediamine

(R)-and DAIPEN (2R)-(-)-1,1-two (4-methoxyphenyl)-3-methyl isophthalic acid, 2-butanediamine

(S, S)-DPEN (1S, 2S)-(-)-1, the 2-diphenyl ethylene diamine

(S)-(+)-MTPACI (S)-(+)-a-methoxyl group-a-(trifluoromethyl) phenyl chloroacetic chloride

The DIAD diisopropyl azodiformate

The DMSO dimethyl sulfoxine

The THF oxolane

The DMF dimethyl formamide

TBTU O-benzotriazole-1-base-N, N, N ', N '-tetramethylurea  tetrafluoroborate

The optical purity of formula 1,2 and 17 chemical compounds is measured by electrocapillary phoresis (CE) and/or high pressure liquid chromatography (HPLC).Each embodiment has provided the experiment condition by the HPLC enantiomer separation in experimental section.Separation by CE is carried out with a kind of following experiment setting:

Device: Agilent CE-3D

Capillary tube: method A:64.5cm * 50 μ m, bubble chamber (Agilent)

Method B:64.5cm * 75 μ m, bubble chamber (Agilent)

Buffer: two kinds of methods: 50mM sodium phosphate, pH 2.5 (Agilent)

Chirality selector: two kinds of method: 40mM seven (2,3,6-three-O-methyl)-beta-schardinger dextrin-(Cyclolab)

Voltage: two kinds of method: 30kV

Temperature: two kinds of methods: 10 ℃

Experimental section has provided the number that is used for the corresponding method of analyzing in bracket.

Also measure the purity of formula 4 prochiral ketones of the substrate that reacts as asymmetric catalytic hydrogenation by HPLC.Adopt following experimental implementation:

Post: 150 * 4.6mm XTerra RP, 185 μ m; Mobile phase; 0.01M KH ₂PO ₄(pH2.0)/90: 10: 0 (v/v/v) [0 minutes] of acetonitrile/water are to 15: 80: 5 (v/v/v) [30 minutes]; Flow velocity: 1.0ml/ minute; 30 ℃.For each embodiment, the retention time of title compound (detecting at 237-245nm) provides in experimental section.

All HPLC posts that are used to prepare with analysis purpose all are commercially available:

·CHIRALPAK ^AD，CHIRALPAK ^AD-H，CHIRALPAK ^AS-V，CHIRALPAK ^AS-H，CHIRAL-PAK ^50801，CHIRALCEL ^OJ，CHIRALCEL ^OD-H：DAICEL Chemical Industries Ltd，Tokyo orChiral Technologies-Europe SARL，Ilkirch，France

·Lichrochart ^240ChiraDex ^：Merck KgaA，Darmstadt，Germany

·XTerra RP 18：Waters Corporate，Milord，Massachusetts，USA。

If fusing point is measured after compound crystal, the solvent/solvents mixture that has been used for purification provides at bracket.If the NMR that provides (nuclear magnetic resonance, NMR) chemical shift does not have integration, then observed signal overlapping of the signal of corresponding proton of chemical compound and solvent, water or impurity.

I. formula 1 chemical compound

By separating 7H-8,9-dihydro-pyrans is formula 1 chemical compound of the racemic mixture folder acquisition of [2,3-c]-imidazo [1,2-a] pyridine also

1. (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (R, R)-tartrate

By heating with racemic 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (synthetic being described among the WO 03/014123,840mg, 2.40mmol) and L-(+)-tartaric acid (358mg 2.39mmol) is dissolved in isopropyl alcohol (5ml) and the water (5ml).Allow this mixture crystallizing at room temperature 2 days.Isolate formed precipitation (700mg), by chirality HPLC assay determination enantiomeric excess (referring to following, 21%ee).With this solid recrystallization from the mixture [1: 1 (v/v), 14mL] of isopropyl alcohol and water, obtained three batches of crystal: first: 30mg, 73%ee; Second batch: 120mg, 67%ee; First: yield and ee do not measure.Preceding two batches of crystal are merged recrystallization from isopropanol [1: 1 (v/v), 3mL].Measure isolating salt (60mg) and have 88% ee value.With this sample recrystallization from the isopropanol [1: 1 (v/v), 2mL] once more, obtained this title compound pure sample this (4mg, 0.3% yield, 95%ee).Above-mentioned the 3rd batch of crystalline material is added in the mother solution, goes out other this title compound of 23mg (91%ee) by Crystallization Separation.This sample recrystallization from isopropanol [1: 1 (v/v), 0.4mL] has been obtained to have this title compound (10mg, 0.8% yield) of 96%ee.

Analyze by the HPLC that adopts following condition and to measure enantiomeric excess: post: ChiralcelOJ; Eluant: heptane/ethanol/diethylamine=90: 10: 0.2 (v/v/v); Flow velocity: 1.0ml/ minute; Temperature: 40 ℃.(9R)-enantiomer shows 15.5 minutes retention time; (9R)-enantiomer (this title compound) eluted after 18.4 minutes.

¹H-NMR(dmso-d ₆，400MHz)：d＝2.12(m _c，1H)，2.25(s，bs，4H)，2.34(s，3H)，2.49(bs)，2.75(m _c，1H)，2.86，3.00(2s，6H)，4.24(s，2H)，5.26(d，1H)，7.40(m _c，5H)，7.80(s，1H).

2. (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] (fractionation 8.6mmol) is by using 250 * 110mm CHIRALPAK for synthetic being described among the WO 03/014123,3.00g for pyridine-6-formic acid dimethylformamide ^The preparative chromatography of AD 20 μ m posts is finished.Mobile phase is made up of the mixture [50: 50: 0.1 (v/v/v)] of ethanol, methanol and diethylamine.Separate at the flow velocity of room temperature with 500ml/ minute.Wavelength at 300nm detects product.The product that second quilt elutes through evaluation be this title compound ((9S)-enantiomer) (1.38g, 46% yield, 98.7%ee).

Fusing point: 254 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD and 250 * 4.6mm CHIRALPAK ^The combination of AD-H; Mobile phase: ethanol, methanol, diethylamine [50: 50: 0.1 (v/v/v)]; Flow velocity: 1ml/ minute; Room temperature.This title compound (detecting at 240nm) eluted after 9.0 minutes.

Optical activity: [a] ^D ₂₀=-53 ° (c=0.63, dichloromethane).

¹H-NMR(200MHz，dmso-d ₆)：δ＝2.14(m _c，2H)，2.26，2.35(2s，6H)，2.42(m _c)，2.75(m _c，1H)，2.87，3.01(2s，6H)，5.27(dd，1H)，7.43(m _c，5H)，7.79(s，1H).

3. (9S)-3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (fractionation 0.53mmol) is by using 250 * 20mm CHIRALPAK for embodiment xii, 194mg ^The preparative chromatography of AD 10 μ m posts is finished.Mobile phase is made up of normal heptane and alcoholic acid mixture [9: 1 (v/v)].Separate at the flow velocity of room temperature with 20ml/ minute.Wavelength at 330nm detects product.Second enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (90mg, 46% yield, 98.5-98.9%ee).

Fusing point: 178-181 ℃

Be used for the setting of the analytical method that the HPLC of optical purity measures: post: 250 * 4.6mmCHIRALPAK ^AD 10 μ m; Mobile phase: normal heptane/ethanol [9: 1 (v/v)]; Flow velocity: 2ml/ minute; 30 ℃.This title compound (detecting at 220nm) eluted (98.9%ee) after 13.70 minutes.

Measure optical purity: RT=17.6 minute/98.5%ee (A) by CE.

Optical activity: [a] ^D ₂₀=-65 ° (c=56, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.13m _c，1H)，2.25，2.30(m _c，s，4H)，2.44(m _c)，2.80，2.88(m _c，s，4H)，3.01(s，3H)，4.72(bs，2H)，5.06(bs，1H)，5.29dd，1H)，7.42m _c，5H)，7.89(s，1H).

4. (9S)-3-bromo-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 3-bromo-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a]-pyridine-6-formic acid dimethylformamide (fractionation 0.45mmol) is by using 250 * 20mm CHIRALPAK for embodiment xiii, 186mg ^The preparative chromatography of AD 10 μ m posts is finished.Mobile phase is made up of ethanol and methanol mixture [1: 1 (v/v)].Separate at the flow velocity of room temperature with 20ml/ minute.Wavelength at 330nm detects product.Second enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (90mg, 48% yield, 99.1-99.6%ee).

Fusing point: 161-163 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD 10 μ m; Mobile phase: ethanol/methanol [1: 1 (v/v)]; Flow velocity: 1ml/ minute; 30 ℃.This title compound (detecting at 220nm) eluted (99.1%ee) after 6.24 minutes.

Measure optical purity: RT=17.7 minute/99.6%ee (A) by CE.

Optical activity: [a] ^D ₂₀=-54 ° (c=0.51, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.16(m _c，1H)，2.25，2.31(m _c，s，4H)，2.50(m _c)，2.80，2.87(m _c，s，4H)，3.02(s，3H)，5.31(dd，1H)，7.43(m _c，5H)，7.82(m _c，1H).

Elementary analysis: C ₂₀H ₂₀BrN ₃O ₂(414.31) measured value: C 57.98, H 4.87, and N 10.14, and Br 19.29; Measured value: C 57.21, H 4.92, and N 9.90, and Br 18.49.

5. (9S)-3-ethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 3-ethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (fractionation 0.52mmol) is by using 250 * 50mm CHIRALPAK for embodiment xv, 188mg ^The preparative chromatography of 50,801 20 μ m posts is finished.Mobile phase is made up of ethanol.Separate at the flow velocity of room temperature with 120ml/ minute.Wavelength at 250nm detects product.First enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (90mg, 48% yield, 98.6-99.3%ee).

Fusing point: 211-213 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^5080120 μ m; Mobile phase: ethanol; Flow velocity: 1ml/ minute; 30 ℃.This title compound (detecting at 220nm) eluted (99.3%ee) after 9.06 minutes.

Measure optical purity: RT=18.0 minute/98.6%ee (A) by CE.

Optical activity: [a] ^D ₂₀=-82 ° (c=0.54, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝1.10(t，3H)，2.14，2.26(m _c，s，5H)，2.40(m _c)，2.77，2.87，2.88(m _c，q，s，6H)，3.01(s，3H)，526(dd，1H)，7.42(m _c，5H)，7.88(s，1H).

Elementary analysis: C ₂₂H ₂₅N ₃O ₂H ₂The value of calculation of O (363.46+18): C 69.27, and H 7.13, and N 11.01; Measured value: C 69.95, H 6.76, and N 10.69.

6. (9S)-(2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone

(0.53mmol) fractionation is by using 250 * 50mm CHIRALPAK for embodiment xxv, 198mg for racemic (2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone ^The preparative chromatography of 5080120 μ m posts is finished.Mobile phase is made up of ethanol.Separate at the flow velocity of room temperature with 120ml/ minute.Wavelength at 250nm detects product.First enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (90mg, 45% yield, 98.1-98.8%ee).

Fusing point: 269-271 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^5080120 μ m; Mobile phase: ethanol; Flow velocity: 1ml/ minute; 30 ℃.This title compound (detecting at 220nm) is under eluting after 11.93 minutes (98.1%ee).

Measure optical purity: RT=18.8 minute/98.8%ee (A) by CE.

Optical activity: [a] ^D ₂₀=-60 ° (c=0.55, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.85(m _c，4H)，2.14，2.25，2.35(m _c，2s，8H)，2.56(m _c)，2.81(m _c，1H)，3.24(m _c)，3.48(t，2H)，5.26(dd，1H)，7.42(m _c，5H)，7.84(s，1H).

Elementary analysis: C ₂₃H ₂₅N ₃O ₂H ₂The value of calculation of O (375.47+18): C 70.21, and H 6.92, and N 10.68; Measured value: C 71.10, H 6.55, and N 10.51.

7. (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea also

Racemic 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea (fractionation 0.58mmol) is by using 250 * 110mm CHIRALPAK for embodiment xxvi, 196mg ^The preparative chromatography of ASV 20 μ m posts is finished.Mobile phase is made up of the mixture [100: 0.1 (v/v)] of acetonitrile and dimethylamine.Separate at the flow velocity of room temperature with 520ml/ minute.Wavelength at 300nm detects product.First enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (85mg, 43% yield, 98.7-100%ee).

Fusing point: 253 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^ASH; Mobile phase: acetonitrile/dimethylamine [100: 0.1 (v/v)]; Flow velocity: 0.7ml/ minute; 25 ℃.This title compound (detecting at 220nm) eluted (98.7%ee) after 5.34 minutes.

Measure optical purity: RT=18.5 minute/100.0%ee (A) by CE.

Optical activity: [a] ^D ₂₀=-56 ° (c=0.53, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.00(m _c，s)，2.26(m _c，s，4H)，2.37(s，3H)，2.78(m _c，d，4H)，3.00(m _c，1H)，5.24(dd，1H)，7.41(m _c，5H)，7.92(s，1H)，8.32(q，1H).

8. (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-benzoic acid amides also

Racemic 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-benzoic acid amides (fractionation 0.59mmol) is by using 250 * 110mm CHIRALPAK for embodiment xxvii, 189mg ^The preparative chromatography of AD 20 μ m posts is finished.Mobile phase is made up of normal heptane and alcoholic acid mixture [1: 1 (v/v)].Separate at the flow velocity of room temperature with 520ml/ minute.Wavelength at 300nm detects product.Second enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (85mg, 45% yield, 98.2-98.6%ee).

Fusing point: 349-350 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD 10 μ m; Mobile phase: normal heptane/ethanol [7: 3 (v/v)]; Flow velocity: 1.0ml/ minute; 25 ℃.This title compound (detecting at 220nm) eluted (98.2%ee) after 6.38 minutes.

Measure optical purity: RT=18.8 minute/98.6%ee (A) by CE.

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.09(m _c，1H)，2.26(m _c，s，4H)，2.38(s，3H)，2.97(m _c，2H)，5.24(dd，1H)，7.41(bs，m _c，6H)，7.85(bs，1H)，7.98(s，1H).

9. (9S)-2,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 2,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxix, 208mg, fractionation 0.57mmol) is finished by the preparative chromatography of using 250 * 20mm CHIRALPAK  AD-H, 5 μ m posts.Mobile phase is made up of normal heptane and alcoholic acid mixture [85: 15 (v/v)].Separate at the flow velocity of room temperature with 20ml/ minute.Wavelength at 300nm detects product.Second enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (100mg cystose solid, 48% yield,＞99.5%ee).

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD 10 μ m; Mobile phase: normal heptane/ethanol [85: 15 (v/v)]; Flow velocity: 1.0ml/ minute; 25 ℃.This title compound (detecting) at 220nm after 15.96 minutes, elute (＞99.5%ee).

Optical activity: [a] ^D ₂₀=-49 ° (c=0.45, chloroform).

¹H-NMR(dmso-d _s，200MHz)：δ＝2.05(m _c，1H )，2.25(m _c，s，4H)，2.35，2.39(2s，6H)，2.56(m _c)，2.86，2.91(m _c，s，4H)，3.02(s，3H)，5.37(dd，1H)，7.28(m _c，3H)，7.47(m _c，1H)，7.79(s，1H).

10. (9S)-9-(2-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 9-(2-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (fractionation 0.67mmol) is by using 250 * 20mm CHIRALPAK for embodiment xxxi, 247mg ^The preparative chromatography of AD-H 5 μ m posts is finished.Mobile phase is made up of normal heptane and alcoholic acid mixture [85: 15 (v/v)].Separate at the flow velocity of room temperature with 20ml/ minute.Wavelength at 300nm detects product.Second enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (116mg, 47% yield,＞99.5%ee).

Fusing point: 210 ℃

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD 10 μ m; Mobile phase: normal heptane/ethanol [85: 15 (v/v)];

Flow velocity: 1.5ml/ minute; 25 ℃.This title compound (detecting) at 220nm after 11.22 minutes, elute (＞99.5%ee).

Measure optical purity: RT=14.5 minute/99.8%ee (B) by CE.

Optical activity: [a] ^D ₂₀=-84 ° (c=0.47, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.24，225(m _c，s，5H)，2.35(s，3H)，2.54(m _c)，2.84，2.90(m _c，s，4H)，3.02(s，3H)，5.48(dd，1H)，7.29(m _c，2H)，7.44(m _c，1H)，7.58(m _c，1H)，7.81(s，1H).

11. (9S)-and 9-(4-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 9-(4-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (fractionation 0.57mmol) is by using 250 * 20mm CHIRALPAK for embodiment xxxiii, 210mg ^The preparative chromatography of AD-H 5 μ m posts is finished.Mobile phase is made up of normal heptane and alcoholic acid mixture [85: 15 (v/v)].Separate at the flow velocity of room temperature with 20ml/ minute.Wavelength at 300nm detects product.Second enantiomer that elutes through evaluation be this title compound ((9S)-enantiomer) (105mg, 50% yield,＞99.5%ee).

Fusing point: 255 ℃

Flow velocity: 1.5ml/ minute; 35 ℃.This title compound (detecting) at 220nm after 18.79 minutes, elute (＞99.5%ee).

Measure optical purity: RT=14.8 minute/99.8%ee (B) by CE.

Optical activity: [a] ^D ₂₀=-72 ° (c=0.47, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.16，2.25(m _c，s，5H)，2.35(s，3H)，2.48(m _c)，2.79，2.88(m _c，s，4H)，3.01(s，3H)，5.27(dd，1H)，7.26(m _c，2H)，7.54(m _c，2H)，7.79(s，1H).

12. (9S)-2,3-dimethyl-9-thiophene-2-base-7H-8,9-dihydro-pyrans [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

This title compound can be by according to 2 of the method resolution of racemic that is similar to the foregoing description, 3-dimethyl-9-thiophene-2-base-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxv) obtains.

Fusing point: 237-238 ℃ (acetone)

Measure optical purity by CE: RT[(9R)-enantiomer]=15.7 minutes/8.0 areas-%;

RT[(9S)-enantiomer]=16.1 minutes/92.0 areas-%; 84.0%ee (A).

Optical activity: [a] ^D ₂₀=-18 ° (c=0.61, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.25，2.26，2.34(s，m _c，s，8H)，2.53(m _c)，2.73，2.87(m _c，s，4H)，3.01(s，3H)，5.56(dd，1H)，7.08(dd，1H)，7.23(bd，1H)，7.57(dd，1H)，7.79(s，1H).

13. (9S)-and 6-methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine also

This title compound can be by the 6-methoxy-2 according to the method resolution of racemic that is similar to the foregoing description, and 3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine obtain.Corresponding racemic modification can make like this: with sodium borohydride with 3-(8-hydroxyl-6-methoxy-2,3-dimethyl-imidazo [1,2-a] pyridine-7-yl)-1-phenyl-third-1-ketone (EXAMPLE l i) reduction, use a kind of following method with 7-(3-hydroxyl-3-phenyl-propyl group)-6-methoxy-2 then, 3-dimethyl-imidazo [1,2-a] pyridine-8-phenol cyclization.

Fusing point: 146-148 ℃ (ether)

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD-H 5 μ m; Mobile phase: isopropyl alcohol/normal hexane=1: 9 (v/v), contain 0.1% diethylamine; Flow velocity: 1ml/ minute; 35 ℃, detect at 237nm.(9R)-(0.7 area-%) eluted after 12.9 minutes, this title compound eluted (99.3 areas-%) to enantiomer after 19.3 minutes.Optical purity: 98.6%ee.

Optical activity: [a] ^D ₂₀=-98 ° (c=0.61, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.15，2.25，2.35(m _c，2s，8H)，2.83(m _c，2H)，3.30(s)，4.42(s，2H)，5.20(dd，1H)，7.43(m _c，5H)，7.76(s，1H).

Obtain formula 1 chemical compound by asymmetric synthesis

14. (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In the flame-dried flask of filling argon, with (3R)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (EXAMPLE l iii, 9.10g 24.8mmol 85.9%ee) is suspended among the anhydrous THF (330ml).Add triphenylphosphine (19.50g, 74.3mmol) and drip DIAD (15.20g, 75.1mmol) after, obtained dark green solution, with it stirring at room 80 minutes.With this reactant mixture concentrating under reduced pressure, and residue (50g green grease) by purified by flash chromatography [250g silica gel, eluant: ethyl acetate is ethyl acetate/methanol=20: 1 (v/v) then].Obtained colorless solid (6.5g), it has been suspended in the ether (30ml).By filtering precipitation separation, with ether (20ml) washing, and vacuum drying, obtained this title compound of 5.0g (58% yield, optical purity: 85.2-85.4%ee).

Fusing point: 258-260 ℃ (ether)

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD-H 5 μ m; Mobile phase: ethanol/methanol=1: 1 (v/v), contain 0.1% diethylamine; Flow velocity: 1ml/ minute; 35 ℃, detect at 243nm.(9R)-(7.3 areas-%) eluted after 4.0 minutes, this title compound eluted (92.7 areas-%) to enantiomer after 4.4 minutes.Optical purity: 85.4%ee.

Measure optical purity by CE: RT[(9S)-enantiomer]=19.5 minutes/92.6 areas-%;

RT[(9R)-enantiomer]=20.3 minutes/7.4 areas-%; 85.2%ee (A).

The optical purity of this title compound can be improved by crystallization in the presence of L-(+) tartaric acid: with (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (0.88g, 2.5mmol, 85%ee) and L-(+)-tartaric acid (0.37g 2.5mmol) is dissolved in the mixture of heat of isopropyl alcohol (5ml) and water (5ml).Formed solid crystal (950mg), taken out this crystallization, analyzed (91.5%ee), recrystallization from the mixture of isopropyl alcohol (8ml) and water (8ml) by HPLC by filtering.Obtained the salt that about this title compound of 500mg and L-(+)-tartaric acid forms, optical purity is 96%ee, once more it is dissolved in the mixture of isopropyl alcohol (4ml) and water (4ml).This title compound and L-(+)-tartaric salt have been formed, by isolated by filtration come out (about 150mg, 12% yield).By HPLC measure optical purity (＞99%ee).

In another experiment, (85%ee) (1.5mmol) there is crystallization down in 0.21g at L-(+)-tartaric acid from the mixture of ethanol (4ml) and water (15ml) for 0.50g, 1.4mmol with this title compound.Obtained about this title compound of 200mg and L-(+)-tartaric salt (29% yield), optical purity is 96%ee.

Enantiomeric excess is by the HPLC assay determination of adopting following condition: post: Chiralcel OJ; Eluant: heptane/ethanol/diethylamine=90: 10: 0.2 (v/v/v); Flow velocity: 1.0ml/ minute; Temperature: 40 ℃.(9R)-enantiomer shows 15.5 minutes retention time, (9S)-enantiomer (title compound) eluted after 18.4 minutes.

¹H-NMR(dmso-d ₈，400MHz)：d＝2.12(m _c，1H)，2.25(s，bs，4H)，2.34(s，3H)，2.49(bs)，2.75(m _c，1H)，2.86，3.00(2s，6H)，4.24(s，2H)，5.26(d，1H)，7.40(m _c，5H)，7.80(s，1H).

15. (9S)-(2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone

In the flame-dried flask of filling argon, with (3R)-[8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-yl]-pyrrolidine-1-base ketone (EXAMPLE l iv, 750mg, 1.90mmol 87.4%ee) is dissolved among the anhydrous THF (20ml).Add triphenylphosphine (1.50g, 5.7mmol), with this suspension stirring at room 10 minutes.Drip DIAD (1.20g, 5.9mmol) after, obtained yellow solution, with it room temperature stirring at room 1 hour.With this reactant mixture concentrating under reduced pressure, and residue (5g) by purified by flash chromatography [80g silica gel, eluant: ethyl acetate).Obtained colorless solid (410mg), it has been suspended in the ether (5ml).By filtering precipitation separation, with ether washing (3ml), and vacuum drying, obtained this title compound of 360mg (50% yield, optical purity: 87.1-87.5%ee).

Fusing point: 268-270 ℃ (ether)

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^OD-H 5 μ m; Mobile phase: normal hexane/isopropyl alcohol=9: 1 (v/v), flow velocity: 1ml/ minute; 35 ℃, 220 and 240nm detect.(9R)-(6.3/6.3 area-%) eluted after 35.5 minutes, this title compound eluted (93.6/93.7 area-%) to enantiomer after 43.1 minutes.Optical purity: 87.4-87.5%ee.

Measure optical purity by CE: RT[(9S)-enantiomer]=19.7 minutes/93.6 areas-%;

RT[(9R)-enantiomer]=20.4 minutes/6.4 areas-%; 87.2%ee (A).

¹H-NMR(dmso-d ₆，200MHz)：d＝1.85(m _c，4H)，2.13(m _c，1H)，2.25(s，m _c，4H)，2.35(s，3H)，2.50(m _c)，2.81(m _c，1H)，3.26(m _c，2H)，3.48(t，2H)，5.25(dd，1H)，7.42(m _c，5H)，7.84(s，1H).

16. (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea also

In the flame-dried flask of filling argon, with (3R)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea (example I v, 900mg, 2.55mmol 92.0%ee) is suspended among the anhydrous THF (55ml).

Add triphenylphosphine (2.00g, 7.6mmol) and drip DIAD (1.55g 7.6mmol) afterwards, has obtained brown solution, with it stirring at room 1 hour.With this reactant mixture concentrating under reduced pressure, and residue (6g) by purified by flash chromatography [150g silica gel, eluant: methylene chloride=100: 1 (v/v)].Obtained colorless solid, it has been suspended in the ether.Come precipitation separation by filtration, and vacuum drying, this title compound of 120mg (14% yield, optical purity: 94.2%ee) obtained.

Fusing point: 261-263 ℃ (ether)

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD-H 5 μ m; Mobile phase: ethanol/methanol=1: 1 (v/v) has 0.1% diethylamine; Flow velocity: 0.8ml/ minute; 35 ℃, detect at 245nm.(9R)-(2.9 areas-%) eluted after 4.1 minutes, this title compound eluted (97.1 areas-%) to enantiomer after 4.4 minutes.Optical purity: 94.2%ee.

Measure optical purity by CE: RT[(9S)-enantiomer]=18.6 minutes/97.1 areas-%; RT[(9R)-enantiomer]=19.9 minutes/2.9 areas-%; 94.2%ee (A).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.07(m _c，1H)，2.26(s，m _c，4H)，2.37(s，3H)，2.74，2.77(m _c，d，4H)，3.00(m _c，1H)，5.24(dd，1H)，7.42(m _c，5H)，7.91(s，1H)，8.32(bq，1H).

I. formula 2 chemical compounds

By separating 7H-8,9-dihydro-pyrans is formula 2 chemical compounds of the racemic mixture folder acquisition of [2,3-c]-imidazo [1,2-a] pyridine also

A. (9R)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (S, S)-tartrate

By heating with racemic 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (synthetic being described among the WO 03/014123,840mg, 2.40mmol) and L-(+)-tartaric acid (358mg 2.39mmol) is dissolved in isopropyl alcohol (5ml) and the water (5ml).Allow this mixture crystallizing at room temperature 2 days.Remove post precipitation, mother solution is concentrated, handle, with mixture [95: 5 (v/v), the 3 * 150ml] extraction of ethyl acetate/methanol with 1N NaOH (40ml).The organic facies that merges is washed with saline (75ml), with dried over sodium sulfate and concentrating under reduced pressure.Isolate thus and contain 2 of excessive (9R)-enantiomer, 3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] (250mg 31%ee), is dissolved in it in isopropyl alcohol (4ml) and the water (4ml) for the sample of pyridine-6-formic acid dimethylformamide.(107mg 0.71mmol), allows this crystalline mixture to add D-(-)-tartaric acid.Isolate precipitation (75mg, 79%ee), recrystallization from the isopropanol [1: 1 (v/v), 2ml].Obtained this title compound of 14mg (1.1%) (enantiomeric excess＞90%).

Analyze by the HPLC that adopts following condition and to measure enantiomeric excess: post: ChiralcelOJ; Eluant: heptane/ethanol/diethylamine=90: 10: 0.2 (v/v/v); Flow velocity: 1.0ml/ minute; Temperature: 40 ℃.(9R)-enantiomer (this title compound) shows 15.5 minutes retention time; (9R)-enantiomer (embodiment 1) eluted after 19.1 minutes.

¹H-NMR(dmso-d ₆，400MHz)：d ＝2.12(m _c，1H)，2.25(s，bs，4H)，2.34(s，3H)，2.49(bs)，2.75(m _c，1H)，2.86，3.00(2s，6H)，4.23(s，2H)，5.26(d，1H)，7.41(m _c，5H)，7.80(s，1H).

B. (9R)-2,3-dimethyl-9-phenyl-7H-8s9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 2 as carrying out as described in the embodiment 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (syntheticly are described among the WO03/014123 3.00g, fractionation 8.6mmol).First by enantiomer of being eluted through evaluation be this title compound ((9R)-enantiomer) (1.40g, 47% yield, 98.2%ee).

Fusing point: 254 ℃

Be used for being described in embodiment 2 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 240nm) eluted (98.2%ee) after 8.0 minutes.

Optical activity: [a] ^D ₂₀=53 ° (c=0.61, dichloromethane).

C. (9R)-3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans also [2, Scl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

Carry out racemic 3-hydroxymethyl-2-methyl-9-phenyl-7H-8 as described in embodiment 3,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xii, 194mg, fractionation 0.53mmol) also.First enantiomer that elutes through evaluation be this title compound ((9R)-enantiomer) (90mg, 46% yield, 99.6-100%ee).

Fusing point: 178-181 ℃

Be used for being described in embodiment 3 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 220nm) eluted (99.6%ee) after 9.50 minutes.

Measure optical purity: RT=18.0 minute/100%ee (A) by CE.

Optical activity: [a] ^D ₂₀=62 ° (c=0.53, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.13(m _c，1H)，2.25，2.30(m _c，s，4H)，2.44(m _c)，2.80，2.88(m _c，s，4H)，3.01(s，3H)，4.72(bs，2H)，5.06(bs，1H)，5.29(dd，1H)，7.42m _c，5H)，7.89(s，1H).

D. (9R)-3-bromo-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Carry out racemic 3-bromo-2-methyl-9-phenyl-7H-8 as described in embodiment 4,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xiii, 186mg, fractionation 0.45mmol) also.First enantiomer that elutes through evaluation be this title compound ((9R)-enantiomer) (90mg, 48% yield, 99.7-99.8%ee).

Fusing point: 162-164 ℃

Be used for being described in embodiment 4 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 220nm) eluted (99.8%ee) after 4.76 minutes.

Measure optical purity: RT=18.0 minute/99.7%ee (A) by CE.

Optical activity: [a] ^D ₂₀=64 ° (c=0.45, chloroform filtered sample before measuring optical activity via silicagel pad).

Elementary analysis: C ₂₀H ₂₀BrN ₃O ₂(414.31) value of calculation: C 57.98, H 4.87, and N 10.14, and Br 19.29; Measured value: C 57.09, H 4.91, and N 9.85, and Br 18.78.

E. (9R)-3-ethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Carry out racemic 3-ethyl-2-methyl-9-phenyl-7H-8 as described in embodiment 5,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xv, 188mg, fractionation 0.52mmol) also.Second enantiomer that elutes through evaluation be this title compound ((9R)-enantiomer) (90mg, 48% yield, 99.4-100%ee).

Fusing point: 212-214 ℃

Be used for being described in embodiment 5 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 220nm) eluted (99.4%ee) after 13.99 minutes.

Measure optical purity: RT=18.7 minute/100.0%ee (A) by CE.

Optical activity: [a] ^D ₂₀=58 ° (c=0.52, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：d＝1.10(t，3H)，2.14，2.26(m _c，s，5H)，2.40(m _c)，2.77，2.87，2.88(m _c，q，s，6H)，3.01(s，3H)，5.26(dd，1H)，7.42(m _c，5H)，7.88(s，1H).

Elementary analysis: C ₂₂H ₂₅N ₃O ₂H ₂The value of calculation of O (363.46+18): C 69.27, and H 7.13, and N 11.01; Measured value: C 69.52, H 6.74, and N 10.45.

F. (9R)-(2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone

As described in embodiment 6, carry out racemic (2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone (embodiment xxv, 198mg, fractionation 0.53mmol).Second enantiomer that elutes through evaluation be this title compound ((9e-enantiomer) (and 90mg, 45% yield, 98.6-98.9%ee).

Fusing point: 246 ℃

Be used for being described in embodiment 6 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 220nm) eluted (98.9%ee) after 18.26 minutes.

Measure optical purity: RT=18.8 minute/98.6%ee (A) by CE.

Optical activity: [a] ^D ₂₀=45 ° (c=0.55, chloroform).

Elementary analysis: C ₂₃H ₂₅N ₃O ₂H ₂The value of calculation of O (375.47+18): C 70.21, and H 6.92, and N 10.68; Measured value: C 70.77, H 6.58, and N 10.31.

G. (9R)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea also

Racemic 2 as carrying out as described in the embodiment 7,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea (embodiment xxvi, 196mg, fractionation 0.58mmol) also.Second enantiomer that elutes through evaluation be this title compound ((91)-enantiomer) (85mg, 43% yield, 96.5-97.0%ee).

Fusing point: 250-253 ℃

Be used for being described in embodiment 7 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 220nm) eluted (96.5%ee) after 6.11 minutes.

Measure optical purity: RT=19.4 minute/97.0%ee (A) by CE.

Optical activity: [a] ^D ₂₀=56 (c=0.53, chloroforms).

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.09(m _c，s)，2.26(m _c，s，4H)，2.37(s，3H)，2.78(m _c，d，4H)，3.00(m _c，1H)，5.24(dd，1H)，7.41(m _c，5H)，7.92(s，1H)，8.32(q，1H).

H. (9R)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-benzoic acid amides also

Racemic 2 as carrying out as described in the embodiment 8,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-benzoic acid amides (embodiment xxvii, 189mg, fractionation 0.59mmol) also.First enantiomer that elutes through evaluation be this title compound ((9R)-enantiomer) (85mg, 45% yield, 98.5-100.0%ee).

Fusing point: 349-350 ℃

Be used for being described in embodiment 8 by the analytical method of HPLC mensuration optical purity.This title compound (detecting at 220nm) eluted (98.5%ee) after 4.90 minutes.Measure optical purity: RT=18.8 minute/100.0%ee (A) by CE.

I. (9R)-2,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Racemic 2 as carrying out as described in the embodiment 9,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxix, 208mg, fractionation 0.57mmol) also.First enantiomer that elutes through evaluation be this title compound ((gR)-enantiomer) (100mg cystose solid, 48% yield,＞99.5%ee).

The setting that is used for measuring by HPLC the analytical method of optical purity is described in embodiment 9.This title compound (detecting) at 220nm after 10.84 minutes, elute (＞99.5%ee).

Optical activity: [a] ^D ₂₀=39 ° (c=0.42, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.05(m _c，1H)，2.25(m _c，s，4H)，2.35，2.39(2s，6H)，2.56(m _c)，2.86，2.91(m _c，s，4H)，3.02(s，3H)，5.37(dd，1H)，7.28(m _c，3H)，7.47(m _c，1H)，7.79(s，1H).

J. (9R)-9-(2-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Carry out racemic 9-(2-fluorophenyl)-2 as described in embodiment 10,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxi, 247mg, fractionation 0.67mmol) also.First enantiomer that elutes through evaluation be this title compound ((9R)-enantiomer) (117mg, 47% yield,＞99.5%ee).

Fusing point: 210 ℃

The setting that is used for measuring by HPLC the analytical method of optical purity is described in embodiment 10.This title compound (detecting) at 220nm after 8.41 minutes, elute (＞99.5%ee).

Measure optical purity: RT=15.1 minute/99.8%ee (B) by CE.

Optical activity: [a] ^D ₂₀=75 ° (c=0.47, chloroform).

¹H-NMR(dmso-d ₆，200MHz)：δ＝2，24，2.25(m _c，s，5H)，2.35(s，8H)，2.54(m _c)，2.84，2.90(m _c，s，4H)，3.02(s，3H)，5.48(dd，1H)，7.29(m _c，2H)，7.44(m _c，1H)，7.58(m _c，1H)，7.81(s，1H).

K. (9R)-9-(4-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

Carry out racemic 9-(4-fluorophenyl)-2.3-dimethyl-7H-8 as described in embodiment 11,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxiii, 210mg, fractionation 0.57mmol) also.First enantiomer that elutes through evaluation be this title compound ((9R)-enantiomer) (105mg, 50% yield,＞99.5%ee).

Fusing point: 255 ℃

The setting that is used for measuring by HPLC the analytical method of optical purity is described in embodiment 11.This title compound (detecting) at 220nm after 10.59 minutes, elute (＞99.5%ee).

Measure optical purity: RT=15.1 minute/98.2%ee (B) by CE.

Optical activity: [a] ^D ₂₀=60 (c=0.39, chloroforms).

Obtain formula 2 chemical compounds by asymmetric synthesis

L. (9R)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In the flame-dried flask of filling argon, with (3S)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (EXAMPLE l ii, 4.00g 10.9mmol 95.4%ee) is dissolved in the anhydrous methylene chloride (80ml), the adding triphenylphosphine (4.30g, 16.4mmol).(3.40g 16.8mmol), has at this moment obtained yellow-green soln to add DIAD with 3 minutes.Add finish after immediately with this reactant mixture concentrating under reduced pressure, by by purified by flash chromatography residue [100g silica gel, eluant: methylene chloride=100: 1 is 20: 1 (v/v) then].Obtained solid (4g), it has been suspended in the acetone (20ml), by filtering precipitation separation, with acetone (5ml) and ether (10ml) washing, and vacuum drying, obtained this title compound of 1.6g (42% yield, optical purity: 95.6-95.8%ee).

Fusing point: 257-259 ℃ (acetone)

It is as follows to be used for being provided with of analytical method that the HPLC of optical purity measures: post: 250 * 4.6mm CHIRALPAK ^AD-H 5 μ m; Mobile phase: ethanol/methanol=1: 1 (v/v), contain 0.1% diethylamine; Flow velocity: 1ml/ minute; 35 ℃, detect at 243nm.(97.8 areas-%) eluted after 3.9 minutes, (9S) enantiomer eluted (2.2 areas-%) to this title compound after 4.4 minutes.Optical purity: 95.6%ee.

Measure optical purity by CE: RT[(9S)-enantiomer]=18.3 minutes/2.1 areas-%;

RT[(9R)-enantiomer]=18.6 minutes/97.9 areas-%; 95.8%ee (A).

¹H-NMR(dmso-d ₆，200MHz)：d＝2.14(m _c，1H)，2.26(s，m _c，4H)，2.35(s，3H)，2.47(m _c)，2.78，2.87(m _c，s，4H)，3.01(s，3H)，5.26(dd，1H)，7.42(m _c，5H)，7.79(s，1H).

III. raw material and intermediate

By the synthetic racemic 7H-8 of cross substitution reaction, 9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine compounds also

I.2-amino-3-benzyloxy-5-bromo-pyridine

(85.0g 0.42mol) is dissolved in 10% aqueous sulfuric acid (1000ml) with 2-amino-3-benzyloxy pyridine.This yellow solution is cooled to 0-4 ℃, and (80.5g was 0.50mol) at acetic acid (276g, 4.6mol) solution in 2 hours dripping bromine.Obtained red suspension, it was stirred 2.5 hours at 0 ℃, poured into then in the mixture of frozen water (500ml) and dichloromethane (1000ml).By adding 25% ammonia spirit (about 600ml) in the biphase mixture that is well stirring to this pH value is adjusted to 8.Separate each with water, with dichloromethane (3 * 500ml) aqueous phase extracted.Wash the organic facies that merges with water (400ml), and use dried over sodium sulfate.Removal of solvent under reduced pressure and with residue by purified by flash chromatography [1kg silica gel, eluant: petrol ether/ethyl acetate=7: 3 (v/v)].Be separated to this title compound of 96.0g thus, be brown solid (81% yield).

Fusing point: 109-110 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝4.73(bs，2H)，5.04(s，2H)，7.08(d，1H)，7.40(m _c，5H)，7.73(d，1H).

Ii.8-benzyloxy-6-bromo-2-methyl-imidazo [1,2-a] pyridine

With 2-amino-3-benzyloxy-5-bromo-pyridine (96.0g, 0.34mol) and chlroacetone (0.63mol) the good solution that is stirring in anhydrous THF (300ml) is heated to 60 ℃ for 50ml, 58.0g.3.5 after it, by filtering to isolate during reaction formed precipitation, with THF (30ml) washing, and vacuum drying.With mother solution reuse chlroacetone (50ml, 58.0g 0.63mol) handle, with this reactant mixture 60 ℃ of restir 8 days.Formed precipitation again, once more by filtering to isolate precipitation, with THF (30ml) washing, and vacuum drying.These two batches of products (55+48g) are merged crystallization from the isopropyl alcohol (800ml) of heat.The clear crystal (55g) that is obtained is dissolved in the biphase mixture of water and dichloromethane.By adding 6N sodium hydrate aqueous solution this mixture that neutralizes.Separate each mutually also with dichloromethane (2 * 50ml) aqueous phase extracted.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.The gained solid is passed through purified by flash chromatography [1.7kg silica gel, eluant: petrol ether/ethyl acetate=8: 2 (v/v)].The mother solution of crystallisation step is concentrated, as mentioned above purification residue (48g).Be separated to 63.7g (59% yield) viscosity yellow solid altogether, H-NMR the analysis showed that it is this pure title compound.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.43(s，3H)，5.28(s，2H)，6.52(d，1H)，7.37(m _c，6H)，7.79(d，1H).

Iii.8-benzyloxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With the 8-benzyloxy-6-bromo-2-methyl-imidazo [1,2-a] pyridine (146.0g, 0.46mol) transfer in the autoclave by the solution in anhydrous THF (3l).Add acid chloride (11.5g, 0.05mol), triphenylphosphine (71.0g, 0.27mol), triethylamine (132ml, 0.94mol) and the solution of 2M dimethylamine in THF (1.2l, 2.4mol) back to autoclave pressurization (6 crust), and is heated to 120 ℃ with carbon monoxide.After 18 hours,, filter this reactant mixture cooling, and vacuum concentration.Residue is dissolved in dichloromethane (700ml) and the water (300ml).Separate each phase, with dichloromethane extraction water (100ml).With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Obtained the brown residue of viscosity (219g), with it by purified by flash chromatography (4.4kg silica gel, eluant: ethyl acetate is ethyl acetate/methanol=9: 1 then).Be separated to this title compound, be ecru solid (110g, 77% yield), by ¹H-NMR spectrum shows that it is pure.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.47(s，3H)，2.95(bs，6H)，5.35(s，2H)，6.43(d，1H)，7.40(m _c，6H)，7.88(d，1H).

Iv.8-hydroxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

(58.0g, 0.19mol) (7g) handle, and applies the hydrogen-pressure of 1 crust by 10% palladium carbon with hydrogenation catalyst for the solution in methanol (500ml) with 8-benzyloxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide.With this suspension in stirring at room after 18 hours, by removing by filter catalyst, with the filtrate vacuum concentration.Isolate this title compound (40.1g, 98% yield), be the ecru solid.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.44(s，3H)，3.10(bs，6H)，6.74(d，1H)，7.31(s，1H)，7.89(d，1H)，8.96(bs，1H).

V.8-allyloxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With pure 8-hydroxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (4.74g, 21.6mmol) be dissolved in the dry DMF (50ml), add potassium carbonate (2.98g, 21.6mmol) and allyl bromide, bromoallylene (3.14g, 25.9mmol), with this reactant mixture stirring at room 18.5 hours.Removal of solvent under reduced pressure and residue is dissolved in saturated ammonium chloride solution (100ml) and the chloroform (150ml).Separate each mutually and with chloroform (2 * 150ml) aqueous phase extracted.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Gained dark-brown liquid (8.5g) is passed through purified by flash chromatography [250g silica gel, eluant: ethyl acetate/methanol=4: 1 (v/v)].Isolate this title compound (5.05g) with 70% yield, be yellow oil. ¹H-NMR spectrum can be seen and have trace impurity (about 5mol-%).

¹H-NMR(CDCl ₃，200MHz)：δ＝2.46(s，3H)，3.09(s，6H)，4.79(dt，2H)，5.33(dd，1H)，5.45(dd，1H)，6.15(ddt，1H)，6.48(d，1H)，7.33(s，1H)，7.87(d，1H).

Vi.7-pi-allyl-8-hydroxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

To only contain that 8-allyloxy-2-methyl-imidazo [1,2-a] pyridine-(3.93g, flask 15.2mmol) place the oil bath that is heated to 160 ℃ in advance to 6-formic acid dimethylformamide.After 50 minutes, this reaction mixture cured has formed dark brown solid 160 ℃ of maintenances.This crude product is cooled to room temperature, handles with the mixture [1: 1 (v/v), 20ml] of acetone and ether.Be settled out colorless solid, by filtering to isolate, with ether washing (10ml), and vacuum drying.Be separated to this pure title compound of 2.10g thus.With the mother solution concentrating under reduced pressure, and by purified by flash chromatography (70g silica gel, eluant: ethyl acetate/methanol=9: 1 is 4: 1 (v/v) then], obtained this title compound of 0.48g (2.58g, total recovery is 66%) again.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.43(s，3H)，2.88(s，3H)，3.11(s，3H)，3.55(bd，2H)，5.00，5.07(2dd，2H)，5.98(m _c，1H)，7.22(s，1H)，7.53(s，1H)，9.57(bs，1H).

Vii. neopentanoic acid (7-pi-allyl-6-formyl-dimethylamino-2-methyl-imidazo [1,2-a] pyridine-8-yl) ester

To pure 7-pi-allyl-8-hydroxy-2-methyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (1.00g, 3.9mmol) add in the suspension in acetone (30ml) potassium carbonate (0.53g, 3.9mmol) and pivalyl chloride (0.93g, 7.7mmol).With this yellow suspension stirring at room 3 hours.After adding saturated ammonium chloride solution (20ml) and water (10ml), (3 * 50ml) extract with dichloromethane with this reactant mixture.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Crude product (1.46g anhydrous solid) is passed through purified by flash chromatography (30g silica gel, eluant: ethyl acetate).Yield with 72% has obtained this title compound (0.96g anhydrous solid).

Fusing point: 178-180 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝1.48(s，9H)，2.41(s，3H)，2.89(s，3H)，3.08(s，3H)，3.35(d，2H)，5.04(m _c，2H)，5.78(m _c，1H)，7.28(s，1H)，7.82(s，1H).

Viii. (E)-neopentanoic acid [6-formyl-dimethylamino-2-methyl-7-(3-phenyl-pi-allyl)-imidazo [1,2-a] pyridine-8-yl] ester

(9.30g 27.1mmol) is dissolved in the dichloromethane (140ml) of using argon-degassed ester with alkene neopentanoic acid (7-pi-allyl-6-formyl-dimethylamino-2-methyl-imidazo [1,2-a] pyridine-8-yl).(19.53g, 108.4mmol) (1.08mmol 4.mol-%), has obtained red solution for CAS 246047-72-3,920mg with second filial generation Grubbs catalyst to add trans stilbene.This reactant mixture is heated to 40 ℃, under this temperature, stirred 18 hours.To pass through purified by flash chromatography [1.2kg silica gel, eluant: petroleum ether (to remove excessive trans stilbene) is ethyl acetate then] by this green solution being concentrated the crude product that obtains.Isolated light green color solid (6.6g); it is by this title compound (90mol-%; 53% yield) and unconverted neopentanoic acid (7-pi-allyl-6-formyl-dimethylamino-2-methyl-imidazo [1,2-a] pyridine-8-yl) ester (10mol-%, ratio be by ¹The H-NMR assay determination) composition.

From with this title compounds of 9: 1 mixture of unconverted raw material ¹The H-NMR data

(CDCl ₃，200MHz)：δ＝1.49(s，9H)，2.42(s，3H)，2.79(s，3H)，3.01(s，3H)，3.53(d，2H)，6.12(dt，1H)，δ.43(d，1H)，7.24(m _c，6H)，7.81(s，1H).

Above the NMR signal of raw material is reported in.

Ix.2-methyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

To contain (E)-neopentanoic acid [6-formyl-dimethylamino-2-methyl-7-(3-phenyl-pi-allyl)-imidazo [1; 2-a] pyridine-8-yl] ester (6.05g; 14.4mmol) and neopentanoic acid (7-pi-allyl-6-formyl-dimethylamino-2-methyl-imidazo [1; 2-a] pyridine-8-yl) ester (0.55g, handle with 200ml orthophosphoric acid (85%) by the product (6.6g) of above-mentioned cross substitution reaction 1.6mmol).The gained green solution was heated 50 minutes at 80 ℃.This reactant mixture is cooled to room temperature,, neutralizes with the 6N sodium hydroxide solution at 0 ℃ with dichloromethane (200ml) dilution.Separate each phase, and with dichloromethane (2 * 200ml) aqueous phase extracted.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Crude product is passed through purified by flash chromatography [210g silica gel, eluant: ethyl acetate/methanol=9: 1 (v/v)].Obtained colorless solid (4.4g, 91% yield), ¹H-NMR the analysis showed that it is this pure title compound.

Fusing point: 189 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝2.26(m _c，2H)，2.41(s，3H)，2.58，2.77(2m _c，2H)，2.94(s，3H)，3.12(s，3H)，5.31(dd，1H)，7.40(m _c，6H)，7.67(s，1H).

X. by one kettle way Synthetic 2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

This title compound also can obtain by one kettle way: in the flame-dried flask of filling argon; with neopentanoic acid (7-pi-allyl-6-formyl-dimethylamino-2-methyl-imidazo [1; 2-a] pyridine-8-yl) (4.80g 14.0mmol) is dissolved in the dichloromethane (100ml) of using argon-degassed ester.(10.10g, 56.0mmol) (0.56mmol 4mol-%) afterwards, is heated to 40 ℃ with this solution for CAS 246047-72-3,475mg with second filial generation Grubbs catalyst to add trans stilbene.This reactant mixture was stirred 18 hours under this temperature, then concentrating under reduced pressure.Obtained green solution, it has been handled with 100ml orthophosphoric acid (85%).This suspension is heated to 80 ℃.After 1 hour, obtained settled solution, it has been cooled to room temperature, poured in the mixture of frozen water (50ml) and dichloromethane (50ml).By adding the 6N sodium hydroxide solution pH value is adjusted to 8.Separate each mutually also with dichloromethane (2 * 20ml) aqueous phase extracted.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Residue 16g green solid is passed through purified by flash chromatography [320g silica gel, eluant: petroleum ether (to remove excessive trans stilbene) is ethyl acetate l methanol=100: 2 (v/v) then].Be separated to this title compound (3.0g, 64% yield), be green foam shape solid.By ¹H-NMR spectrum shows that it is pure.

Xi.3-formoxyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c] imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

The flask that will contain dry DMF (10ml) is cooled to 0 ℃, and the adding phosphorus oxychloride (1.14g, 7.4mmol).Remove cooling bath, with this solution stirring at room 1 hour.Should the redness reactant mixture with 2-methyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c] imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (1.00g, 3.0mmol) solution-treated in dry DMF (10ml), and be heated to 60 ℃ also.After 3 hours, this reactant mixture is poured on the frozen water (50ml), neutralizes by adding the 2N sodium hydroxide solution, (3 * 40ml) remove to use dichloromethane then.With the organic facies dried over sodium sulfate that merges, and vacuum concentration.Obtain this title compound (1.0g, 92% yield), be brown solid, by ¹H-NMR spectrum shows that it almost is pure.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.31(m _c，2H)，2.72(s，m _c，4H)，2.80，2.95(m _c，s，4H)，3.15(s，3H)，5.34(dd，1H)，7.39(m _c，5H)，9.09(s，1H)，9.99(s，1H).

Xii.3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

With 3-formoxyl-2-methyl-9-phenyl-7H-8; 9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (1.00g also; 2.8mmol) (52mg 1.37mmol) handles with sodium borohydride for suspension in dehydrated alcohol (30ml).With this reactant mixture stirring at room 40 minutes.Obtained settled solution, be poured on water (20ml) and the dichloromethane (50ml).Separate each phase, (2 * 20ml) extract with dichloromethane with water.

With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Obtained light yellow cystose solid, with its crystallization from acetone (5ml).By filtering to isolate colourless precipitation, and vacuum drying, pure this title compound (42% yield) of 420mg obtained.Mother solution is concentrated, and residue is passed through purified by flash chromatography [silica gel, eluant: ethyl acetate/methanol=10: 1 (v/v)].Obtained again this title compound of 160mg (16% yield, yellow solid, ¹H-NMR spectrum shows that it is pure).

Fusing point: 186 ℃ (acetone)

¹H-NMR(CDCl ₃，200MHz)：δ＝2.30，2.37(m _c，s，5H)，2.68(m _c，2H)，2.90，3.10(2s，6H)，4.85(s，2H)，5.30(dd，1H)，7.38(m _c，5H)，7.81(s，1H).

Xiii.3-bromo-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

With 2-methyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment ix/x, 2.00g 6.0mmol) are dissolved in the mixture of chloroform (10ml) and dichloromethane (10ml).This solution is cooled to-78 ℃, and adding N-bromine butanimide (1.06g, 6.0mmol).This reactant mixture is stirred in-78 ℃ to be stirred 45 minutes.Remove cooling bath, add saturated sodium bicarbonate solution (15ml).Separate each phase, water is extracted with dichloromethane (10ml).With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Isolate light green color cystose solid (2.7g), it is passed through purified by flash chromatography [80g silica gel, eluant: ethyl acetate/petroleum ether=6: 4 (v/v)].Isolate this title compound, be ecru solid (1.75g, 71% yield), ¹H-NMR spectrum shows that it is pure.In addition, also be separated to this title compound of 0.5g (96 weight-%) and butanimide (mixture (19% yield) of 4 weight-%).

Fusing point: 167-168 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝2.28(m _c，2H)，2.45(s，3H)，2.69(m _c，2H)，2.93，3.14(2s，6H)，5.32(dd，1H)，7.38(m _c，5H)，7.65(s，1H).

Xiv.2-methyl-9-phenyl-3-vinyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In filling the flame-dried flask of argon, with 3-bromo-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (1.60g, 3.9mmol) be dissolved in anhydrous 1, in the 4-dioxane (50ml).(1.48g, 4.7mmol) (270mg 0.38mmol) handles, and stirs under the temperature of 100 ℃ (pre-warmed oil baths) with chlorination two (triphenylphosphinyl) palladium with tributyl (vinyl) stannane with this solution.After 2 hours, add again a part of tributyl (vinyl) stannane (0.70g, 2.2mmol) and chlorination two (triphenylphosphinyl) palladium (140mg, 0.20mmol).This is reflected at 100 ℃ continued 1 hour.This reactant mixture is cooled to room temperature, in the presence of silica gel (3g), concentrates.Crude product is by purified by flash chromatography [120g silica gel, eluant: petroleum ether is petrol ether/ethyl acetate=1: 1 (v/v) then, is petrol ether/ethyl acetate=2: 8 (v/v) afterwards].In order to realize further purification, after chromatogram purification, this title compound (1.3g) that is obtained is dissolved in ethyl acetate (20ml) and the water (15ml).By adding 2N hydrochloric acid pH value is adjusted to 1.5.Separate each phase, with ethyl acetate (10ml) aqueous phase extracted.Discard organic facies, add dichloromethane (20ml) to aqueous phase.By adding the 2N sodium hydroxide solution pH value is adjusted to 8.Separate each phase, with dichloromethane (2 * 10ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.With residue 1.0g yellow solid vacuum drying, it is pure this title compound (72% yield) after measured.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.30(m _c，2H)，2.54，2.63(s，m _c，4H)，2.79(m _c，1H)，2.92，3.13(2s，6H)，5.34(dd，1H)，5.42(d，1H)，5.56(d，1H)，6.78(dd，1H)，7.38(m _c，5H)，7.75(s，1H).

Xv.3-ethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

With 2-methyl-9-phenyl-3-vinyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (0.280g 0.77mmol) is dissolved in the absolute methanol (20ml).Add Lindlar catalyst (Pd/CaCO ₃/ Pb, Aldrich 20,573-7,56mg, 20 weight-%), apply the Hydrogen Vapor Pressure of 1 crust.This reactant mixture is stirred in stirring at room 2 hours, adds the 28mg (catalyst of 10 weight-%) again.Hydrogenation continued 2 hours.

By removing by filter catalyst, filtrate is concentrated, remaining yellow solid vacuum drying.Yield with 89% has been separated to this title compound (250mg).

Fusing point: 230 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝1.20(t，3H)，2.26(m _c，2H)，2.41(s，3H)，2.57(m _c，1H)，2.73，2.84，2.92(m _c，q，s，6H)，3.13(s，3H)，5.32(dd，1H)，7.38(m _c，6H).

Elementary analysis: C ₂H ₂₅N ₃O ₂(363.46) value of calculation: C 72.70, H 6.93, and N 11.56;

Measured value: C 71.71, H 6.86, and N 11.21.

Xvi.2,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In the flame-dried flask of filling argon, with 7-pi-allyl-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl-propyl group)-siloxy]-imidazo [1,2-a] (embodiment xxi, 1.50g 3.6mmol) are dissolved in the dichloromethane (50ml) of using argon-degassed pyridine-6-formic acid dimethylformamide.(2.13g, 18.0mmol) (0.14mmol 4mol-%) afterwards, is heated to 40 ℃ with this solution for CAS 246047-72-3,122mg with second filial generation Grubbs catalyst to add o-methyl styrene.This reactant mixture was stirred 4 days under this temperature, then concentrating under reduced pressure.The suspension of this residue in 80ml orthophosphoric acid (85%) stirred in 80 ℃ (pre-warmed oil baths).1.5 after hour, obtained clear solutions, this solution poured on the frozen water (100ml).By adding the 6N sodium hydroxide solution pH value is adjusted to 8.All dichloromethane (3 * 80ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Solid residue (3.7g) is passed through purified by flash chromatography [120g silica gel, eluant: petroleum ether (to remove 2,2 '-dimethyl stilbene) is ethyl acetate/triethylamine=100: 1 (v/v) then].Remove desolvate after, obtained two samples: (A) pure this title compound (280mg cystose solid, 21% yield); (B) this title compound and 2,3,8-trimethyl-7,8-dihydro-furan be the mixture of [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (cyclization of the raw material by deprotection forms, 240mg cystose solid) also.This mixture is further purified by preparation HPLC, has obtained the pure title compound (gross production rate: 29%) of 111mg again.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.18(m _c，2H)，2.36，2.37，2.40(3s，9H)，2.78，2.99(m _c，s，5H)，3.15(s，3H)，5.42(dd，1H)，7.20(m _c，3H)，7.43(s，1H)，7.56(m _c，1H).

Xvii.9-(2-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In the flame-dried flask of filling argon, with 7-pi-allyl-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl-propyl group)-siloxy]-imidazo [1,2-a] (embodiment xxi, 2.00g 4.8mmol) are dissolved in the dichloromethane (50ml) of using argon-degassed pyridine-6-formic acid dimethylformamide.(2.94g, 24.1mmol) (0.19mmol 4mol-%), is heated to 40 ℃ with this solution for CAS 246047-72-3,162mg with second filial generation Grubbs catalyst to add 2-fluoro-styrene again.This reactant mixture was stirred 17 hours under this temperature, then concentrating under reduced pressure.The suspension of this residue in 25ml orthophosphoric acid (85%) stirred in 100 ℃ (pre-warmed oil baths).After 2 hours, obtained clear solutions, this solution has been poured on frozen water (70ml) and the dichloromethane (100ml).By adding the 6N sodium hydroxide solution pH value is adjusted to 8.Separate each mutually also with dichloromethane (2 * 50ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Black solid residue (5.6g) is passed through purified by flash chromatography [225g silica gel, eluant: ethyl acetate/triethylamine=100: 1 (v/v)].Except that after desolvating, obtained this pure title compound (1.0g colorless solid, 56% yield).

Fusing point: 202 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝2.27(m _c，2H)，2.36，2.41(2s，6H)，2.61(m _c，1H)，2.82(m _c，1H)，2.95，3.14(2s，6H)，5.60(dd，1H)，7.09(m _c，2H)，7.27(m _c)，7.44(s，1H)，7.60(dt，1H).

Xviii.9-(4-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In the flame-dried flask of filling argon, with 7-pi-allyl-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl-propyl group)-siloxy]-imidazo [1,2-a] (embodiment xxi, 1.50g 3.6mmol) are dissolved in the dichloromethane (50ml) of using argon-degassed pyridine-6-formic acid dimethylformamide.Adding to fluoro-styrene (2.20g, 18.0mmol) and second filial generation Grubbs catalyst (CAS 246047-72-3,122mg, 0.14mmol, 4mol-%) after, this solution is heated to 40 ℃.This reactant mixture was stirred 5 days under this temperature, then concentrating under reduced pressure.The suspension of this residue in 80ml orthophosphoric acid (85%) stirred in 80 ℃ (pre-warmed oil baths).After 2 hours, this reactant mixture is poured on the frozen water (100ml).By adding the 6N sodium hydroxide solution pH value is adjusted to 8.With dichloromethane (3 * 100ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.By purified by flash chromatography residue [100g silica gel, eluant: petroleum ether (to remove 4,4 '-difluoro stilbene) is ethyl acetate then, is ethyl acetate/methanol=10: 1 (v/v) afterwards].Except that after desolvating, be separated to this pure title compound, be light green color solid (280mg, 21% yield).

¹H-NMR(CDCl ₃，200MHz)：δ＝2.24(m _c，2H)，2.36，2.41(2s，6H)，2.68(m _c，2H)，2.93，3.13(2s，6H)，5.27(dd，1H)，7.04(t，2H)，7.43(m _c，3H).

Come the synthetic intermediate that is used for asymmetric hydrogenation by the cross substitution reaction

Xix.8-allyloxy-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With pure 8-hydroxyl-2, (synthetic be described in WO 03/014123,50.0g 0.22mol) is dissolved in the dry DMF (1L) 3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide.Add potassium carbonate (29.7g, 0.22mol) and allyl bromide, bromoallylene (31.2g, 0.26mol), and with this reactant mixture stirring at room 18.5 hours.Removal of solvent under reduced pressure is dissolved in residue in saturated ammonium chloride solution (250ml) and the chloroform (500ml).Separate each mutually and with chloroform extraction water (2 *).With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.Residue is passed through purified by flash chromatography [800g silica gel, eluant: ethyl acetate/methanol=9: 1 (v/v)].Yield with 67% has been separated to this title compound (40.0g), is yellow solid. ¹H-NMR spectrum can be seen and have trace impurity (about 14mol-%).

¹H-NMR(CDCl ₃，400MHz)：δ＝2.39，2.46(2s，6H)，3.10(s，6H)，4.80(dt，2H)，5.33(dd，1H)，5.47(dd，1H)，6.14(ddt，1H)，6.53(d，1H)，7.69(d，1H).

Xx.7-pi-allyl-2,3-dimethyl-8-hydroxyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

To only contain 8-allyloxy-2,3-dimethyl-imidazo [1,2-a] pyridine-(40.0g, flask 0.15mol) place the oil bath that is heated to 160 ℃ in advance to 6-formic acid dimethylformamide.After 160 ℃ kept 50 minutes, this reaction mixture cured had formed dark brown solid.Crude product is cooled to room temperature, handles, be settled out the ecru solid with the mixture [1: 1 (v/v), 200ml] of acetone and ether.After 20 minutes, by filtering to isolate precipitation, with the ether washing, and vacuum drying.Be separated to the pure title compound of 28.0g thus.With the mother solution concentrating under reduced pressure and residue (10g brown solid) by purified by flash chromatography (300g silica gel, eluant: ethyl acetate/methanol=9: 1 (v/v)], by having obtained this title compound of 2.2g (30.2g, total recovery is 76%).

¹H-NMR(CDCl ₃，200MHz)：δ＝2.35，2.44(2s，6H)，2.87，3.13(2s，3H)，3.55(d，2H)，5.02，5.07(2dd，2H)，5.97(m _c，1H)，7.36(s，1H)，10.76(bs，1H).

Xxi.7-pi-allyl-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl propyl group) siloxy]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

In the flame-dried flask of filling argon, with 7-pi-allyl-2,3-dimethyl-8-hydroxyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (3.60g, 13.2mmol) suspension in dry DMF (50ml) with imidazoles (1.52g, 22.3mmol) and chlorine (dimethyl) hexyl monosilane (4.40ml, 4.00g, 22.4mmol, slowly add) handle.Obtained brown solution, stirring at room 1 hour.This reactant mixture is poured on the mixture of ice (20g), saturated ammonium chloride solution (30ml) and dichloromethane (50ml).This biphase mixture is stirred a few minutes, separate each phase, with dichloromethane (2 * 15ml) aqueous phase extracted.With organic facies water (20ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure.Isolate colorless solid (5.10g) by purified by flash chromatography residue 7.5g yellowish-brown grease [150g silica gel, eluant: petrol ether/ethyl acetate 8: 2 (v/v)], by ¹H-NMR spectrum has confirmed that it is pure this title compound (93% yield).

Fusing point: 93-95 ℃

¹H-NMR (CDCl ₃, 200MHz): δ=0.41 (s, 6H), 0.96 (d, 6H), 1.02 (s, 6H), 1.83 (septet, 1H), 2.31,2.36 (2s, 6H), 2.84,3.08 (2s, 6H), 3.50 (m _c, 2H), 4.96 (m _c, 2H), 5.84 (m _c, 1H), 7.36 (s, 1H).

Xxii. (E)-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl-propyl group)-siloxy]-7-(3-phenyl-pi-allyl)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

In the flame-dried flask of filling argon, with 7-pi-allyl-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl-propyl group)-siloxy]-imidazo [1,2-a] (5.00g 12.0mmol) is dissolved in the anhydrous methylene chloride (200ml) of using argon-degassed pyridine-6-formic acid dimethylformamide.Add trans stilbene (8.70g, 48.3mmol) and second filial generation Grubbs catalyst (CAS 246047-72-3,0.40g, 0.5mmol, 3.9mol-%), with the red solution reflux that obtained 19 hours.It is 89ml that this dark-brown reactant mixture is concentrated into volume, is loaded on the post of having filled 200g silica gel.Use mixture [7: 3 (v/v)] this title compound of eluting of petroleum ether and ethyl acetate.Remove and desolvate, with oily residue vacuum drying.Obtained pale red foam (3.70g), it is this title compound (93 weight-%, 58% yield) and dimethyl-(1,1, the 2-trimethyl-propyl group)-silanol (mixture of 7 weight-%) by analysis.From post, also be recovered to 400mg (8% yield) raw material.

¹H-NMR (CDCl ₃, 200MHz): δ=0.44 (s, 6H), 0.97 (d, 6H), 1.03 (s, 6H), 1.88 (septet, 1H), 2.31,2.37 (2s, 6H), 2.75,3.03 (2s, 6H), 3.69 (bs, 2H), 6.20 (dt, 1H), 6.37 (d, J=15.8Hz, 1H), 7.22 (m _c, 5H), 7.34 (s, 1H),

Dimethyl-(1,1,2-trimethyl-propyl group)-silanol:

δ＝0.13(s，6H)，0.87(s，6H)，0.90(d，6H)，1.64(m _c).

Xxiii. (E)-8-hydroxyl-2,3-dimethyl-7-(3-phenyl-pi-allyl)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

In the flask of filling argon, with (E)-2,3-dimethyl-8-[dimethyl-(1,1,2-trimethyl-propyl group)-siloxy]-7-(3-phenyl-pi-allyl)-(1.10g 2.2mmol) is dissolved among the anhydrous THF (20ml) imidazo [1,2-a] pyridine-6-formic acid dimethylformamide.

Add lentamente the solution of 1M tetrabutylammonium in THF (3.30ml, 3.3mmol) after, obtained dark green solution, with it stirring at room 30 minutes.This reactant mixture is poured on the mixture of ice (10g), saturated ammonium chloride solution (15ml) and dichloromethane (30ml).This biphase mixture is stirred a few minutes, separate each phase, with dichloromethane (3 * 10ml) aqueous phase extracted.With organic facies water (20ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure.This oily residue (1.5g) is passed through purified by flash chromatography [15g silica gel, eluant: dichloromethane is methylene chloride=20: 1 (v/v) then].Obtained green solid (900mg), it has been suspended in the ether (10ml), separated by filtering, with ether (10ml) washing, and vacuum drying.Yield with 81% has been separated to pure title compound (630mg light gray solid).

Fusing point: 183-185 ℃ (ether)

¹H-NMR(CDCl ₃，200MHz)：δ＝2.32，2.35(2s，6H)，2.76，2.96(2s，6H)，3.48(d，2H)，5.26(bs)，6.23，6.34(m _c，d，2H)，7.27(m _c，5H)，7.69(s，1H)，

Elementary analysis: C ₂₁H ₂₃N ₃O ₂(349.43) value of calculation: C 72.18, H 6.63, and N 12.03;

Measured value: C71.54, H 6.53, and N 11.77.

By with 7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-Ethyl formate saponification synthesizes racemic 7H-8, and 9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine also:

Xxiv.2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid also

With 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-Ethyl formate (synthetic is described in WO 03/014123,16.7g, 48mmol) usefulness of the suspension in methanol (170ml) and water (35ml) potassium hydroxide (4.5g, 80mmol) handle, and be heated to 50 ℃.React after 2 hours, vacuum is removed methanol.Add entry (400ml) and dichloromethane (300ml), pH value is adjusted to 4.8 (isoelectric point, IPs of this title compound), continue to stir 30 minutes by adding 6N hydrochloric acid.Formed precipitation, added dichloromethane (100ml) and methanol (100ml) postprecipitation and dissolve lentamente.Separate each phase, and with dichloromethane (2 * 50ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, being concentrated into volume is 50ml.After adding ether (100ml), formed colourless precipitation.Continuation was stirred 30 minutes at 0 ℃.By filtering to isolate precipitation, and vacuum drying, pure this title compound (58% yield) of 9.1g obtained.Water is saturated with sodium chloride, with chloroform (1 * 400ml, 2 * 100ml) extractions.With the organic facies dried over sodium sulfate that merges, and vacuum concentration.Warp ¹H-NMR confirms, this pure title compound of residue (2.0g, 13% yield).

Fusing point: 18-320 ℃ (ether)

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.09(m _c，1H)，2.28(s，m _c，4H)，2.40(s，3H)，3.10(m _c，2H)，5.25(dd，1H)，7.43(m _c，5H)，8.32(s，1H)，

Do not see tradable proton.

Elementary analysis: value of calculation C ₁₉H ₁₈N ₂O ₃(H2O) _0.5Value of calculation (322.37+9.0): C 68.87, H 5.78, and N 8.45; Measured value: C68.95, H 5.49, and N 8.40.

Xxv. (2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone

With 2, also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid (1.00g, the 3.1mmol) TBTU of the suspension in dichloromethane (50ml) (1.08g, 3.4mmol) processing of 3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans.After 45 minutes response time of room temperature maintenance, and the adding pyrrolidine (219mg, 253 μ l, 3.08mmol).Obtained clear solutions, with it stirring at room 2.5 hours.Pour this reactant mixture into saturated sodium bicarbonate solution (50ml), separate each phase, and with dichloromethane (2 * 20ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and vacuum concentration.Residue (1.8g) is handled with the acetone (10ml) of heat.Allow this suspension be cooled to room temperature, and stirred 1 hour.By filtering precipitation separation (730mg), further by purified by flash chromatography [silica gel, eluant: ethyl acetate/methanol=90: 3 (v/v)].Corresponding level part is evaporated, obtained residue,, separate by filtering with ether (15ml) washing.Yield with 45% has obtained this title compound (524mg).

Fusing point: 274 ℃ (ether)

¹H-NMR(CDCl ₃，200MHz)：δ＝1.97(m _c，4H)，2.26，2.36，2.41(m _c，2s，8H)，2.62(m _c，1H)，2.84(m _c，1H)，3.24(m _c，2H)，3.65(t，2H)，5.31(dd，1H)，7.38(m _c，6H).

Elementary analysis: value of calculation C ₂₃H ₂₅N ₃O ₂(375.47) C 73.58, H 6.71, and N 11.19;

Measured value: C 73.43, H 6.74, and N 11.19.

Xxvi.2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea also

With 2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid (embodiment xxiv, 1.50g, 4.6mmol) and TBTU (1.40g 4.4mmol) is suspended in the dichloromethane (50ml).After 1 hour response time of room temperature maintenance, and the adding methyl amine (solution of 8.0M in ethanol, 2ml, 16mmol).In 30 minutes, obtained settled solution, with it stirring at room 2 hours.This reactant mixture is poured on the water (20ml), separated each phase, with dichloromethane (10ml) aqueous phase extracted.Wash the organic facies that merges with water (10ml), use dried over sodium sulfate, and vacuum concentration.Residue (1.1g) is passed through purified by flash chromatography [silica gel, eluant: methylene chloride=15: 1 (v/v)].After the level part evaporation accordingly, obtained colorless solid, with its vacuum drying.Yield with 58% has obtained this title compound (0.90g).

Fusing point: 234 ℃

Xxvii.2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-benzoic acid amides also

With 2, also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid (embodiment xxiv, 500mg, the 1.54mmol) TBTU of the suspension in dichloromethane (20ml) (504mg, 1.57mmol) processing of 3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans.40 ℃ of heating 1 hour, allow it be cooled to room temperature then this reactant mixture.In this suspension, feed 30 minutes ammonia.This reactant mixture is poured on the water (20ml), added dichloromethane (30ml), by adding 2N hydrochloric acid pH regulator to 6.In order to help to separate each phase, add 10ml methanol.Separate each phase, and with dichloromethane extraction water (2 * 10ml).With the organic facies dried over sodium sulfate that merges, and vacuum concentration.Be separated to this title compound (310mg, 64% yield), be colorless solid, ¹H-NMR spectrum confirms that it is pure.

Fusing point: 303-305 ℃

Synthesize racemic 7H-8 by ketone reduction and acid catalyzed cyclization/Mitsunobu cyclization, 9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine also

Xxviii.8-hydroxyl-7-[3-hydroxyl-3-(2-aminomethyl phenyl)-propyl group]-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With 8-hydroxyl-2,3-dimethyl-7-[3-(2-aminomethyl phenyl)-3-oxo-propyl group]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxvii, 2.00g, 5.3mmol) be dissolved in the dehydrated alcohol (20ml), with a small amount of mode repeatedly add sodium borohydride (240mg, 6.34mmol).Stirring at room 1 hour, (120mg 3.17mmol) handled with another part sodium borohydride with this reactant mixture.Continue to stir 30 minutes, this reactant mixture is poured on the mixture of ice (50g), saturated ammonium chloride solution (50ml) and dichloromethane (100ml).This biphase mixture was stirred 20 minutes.Separate each phase, with dichloromethane (2 * 10ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Be separated to the crude product (3.2g) of this title compound, be yellow foam, it directly is used as the raw material of embodiment xxix.

¹H-NMR (CDCl ₃+ micro-MeOD, 200MHz): δ=2.00 (bm _c, 2H), 2.16 (s, 3H), 2.35 (s, 3H), 2.55 (s, 3H), 2.91,3.05,3.12 (s, bm _c, s, 8H), 4.81 (dd, 1H), 7.07 (m _c, 4H), 7.51 (d, 1H).

Xxix.2,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

With orthophosphoric acid (85 weight-% 15ml) are heated to 80 ℃, drip 8-hydroxyl-7-[3-hydroxyl-3-(2-aminomethyl phenyl)-propyl group]-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (3.2g derives from the crude product of embodiment xxviii).After 25 minutes response time, this hot solution is poured on frozen water (100ml) and the dichloromethane (100ml).By adding the 6N sodium hydroxide solution pH value of this biphase mixture is adjusted to 6.5.Separate each phase, with dichloromethane (2 * 50ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Crude product has been separated to this title compound of 888mg (yield in two steps is 46%) by purified by flash chromatography [silica gel, eluant: ethyl acetate/methanol=9: 1 (v/v)].

Fusing point: 198 ℃

Xxx.7-[3-(2-fluorophenyl)-3-hydroxyl-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With 7-[3-(2-fluorophenyl)-3-oxo-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxviii, 2.00g, 5.2mmol) be suspended in the dehydrated alcohol (70ml), with a small amount of mode repeatedly add sodium borohydride (200mg, 5.3mmol).This reactant mixture-yellow solution stirring at room 30 minutes, is poured on the mixture of saturated ammonium chloride solution (50ml) and dichloromethane (100ml) then.Separate each phase, with dichloromethane (30ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.With the crude product vacuum drying (2.1g colorless solid) of this title compound, it directly is used as the raw material of embodiment xxxi.

¹H-NMR(CDCl ₃，200MHz)：δ＝1.90(m _c，2H)，2.35，2.56(2s，6H)，2.80，2.95(bs，s，4H)，3.14(s，3H)，3.35(m _c，1H)，4.90(dd，1H)，6.88(m _c，1H)，7.09，7.14(m _c，s，3H)，7.59(m _c，1H).

Xxxi.9-(2-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

With 7-[3-(2-fluorophenyl)-3-hydroxyl-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (2.1g derives from the crude product of embodiment xxx) be dissolved in orthophosphoric acid (85 weight-%, 20ml) in.This suspension is heated 80 ℃ (pre-warmed oil baths).After 30 minutes, obtained settled solution.After 1 hour response time, this hot solution is poured on frozen water (100ml) and the dichloromethane (100ml).By adding the 6N sodium hydroxide solution pH value of this biphase mixture is adjusted to 8.Separate each phase, and with dichloromethane (2 * 40ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Obtained light yellow cystose solid, with its vacuum drying.Yield with 94% has obtained this title compound (1.94g).

Fusing point: 203 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝2.23，2.36，2.41(m _c，2s，8H)，2.61(m _c，1H)，2.83，2.95(m _c，s，4H)，3.14(s，3H)，5.60(dd，1H)，7.09(m _c，2H)，7.27(m _c)，7.44(s，1H)，7.60(dt，1H).

Xxxii.7-[3-(4-fluorophenyl)-3-hydroxyl-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With 7-[3-(4-fluorophenyl)-3-oxo-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxix, 2.24g, 5.8mmol) be dissolved in the dehydrated alcohol (70ml), with a small amount of mode repeatedly add sodium borohydride (220mg, 5.8mmol).This reactant mixture stirring at room 45 minutes, is poured on the mixture of saturated ammonium chloride solution (50ml) and dichloromethane (100ml) then.Separate each phase, with dichloromethane (50ml) aqueous phase extracted.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.With the crude product vacuum drying (2.4g colorless solid) of this title compound, it directly is used as the raw material of embodiment xxxiii.

¹H-NMR (CDCl ₃+ micro-MeOD, 200MHz): δ=1.97 (bm _c, 2H), 2.35 (s, 3H), 2.56 (s, 3H), 2.92,3.14,3.20 (2s, bm _c, 8H), 4.55 (dd, 1H), 6.92 (t, 2H), 7.17 (s, 1H), 7.29 (m _c, 2H).

Xxxiii.9-(4-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide 7-[3-(4-fluorophenyl)-3-hydroxyl-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (2.4g, derive from the crude product of embodiment xxxii) be dissolved in orthophosphoric acid (85 weight-%, 20ml).This suspension is heated 80 ℃ (pre-warmed oil baths).After 30 minutes, obtained settled solution.After 1 hour response time, this hot solution is poured on frozen water (100ml) and the dichloromethane (100ml).

By adding the 6N sodium hydroxide solution pH value of this biphase mixture is adjusted to 8.Separate each phase, and with dichloromethane (2 * 40ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Obtained colorless solid, with its vacuum drying.Yield with 85% has obtained this title compound (1.94g).

Fusing point: 260 ℃

Xxxiv.8-hydroxyl-7-(3-hydroxyl-3-thiophene-2-base-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

With 8-hydroxyl-2,3-dimethyl-7-[3-oxo-3-thiophene-2-base-propyl group]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xl, 2.00g, 5.4mmol) be suspended in the dehydrated alcohol (70ml), with a small amount of mode repeatedly add sodium borohydride (250mg, 6.6mmol).Obtained brown solution, this solution stirring at room 2 hours, has been poured on the mixture of saturated ammonium chloride solution (50ml) and dichloromethane (100ml) then.Separate each phase, and with dichloromethane (30ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.With the crude product vacuum drying (2.0g ecru solid) of this title compound, it directly is used as the raw material of embodiment xxxv.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.09(bs，2H)，2.31(s，3H)，2.48(bs，4H)，2.91，3.14(2s，6H)，3.33(bs，1H)，4.80(t，1H)，6.70(bs)，6.89(m _c，2H)，7.11(m _c，2H).

Xxxv.2,3-dimethyl-9-thiophene-2-base-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide also

In the flame-dried flask of filling argon, 8-hydroxyl-7-(3-hydroxyl-3-thiophene-2-base-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (2.0g derives from the crude product of embodiment xxxiv) is suspended among the anhydrous THF (25ml).Add triphenylphosphine (2.80g, 10.7mmol) and drip DIAD (1.63g 8.1mmol) afterwards, has obtained brown solution, with it stirring at room 15 minutes.With this reactant mixture concentrating under reduced pressure, and residue (8g brown oil) by purified by flash chromatography [260g silica gel, eluant: ethyl acetate, ethyl acetate/methanol=100: 1 and 100: 2 (v/v) then].

Obtained colorless solid (title compound that 661mg is pure, 35% yield).

Fusing point: 241

Synthesizing of prochiral ketones:

Xxxvi.8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

(A) in the flame-dried flask of filling argon, with pure 8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (synthetic being described among the WO 03/014123,50.0g, 214mmol) the suspension iodate N in anhydrous methylene chloride (1.2L), (40.3g 218mmol) handles N-dimethylated methylene base imonium.With this reactant mixture stirring at room 1 hour.When beginning, obtained settled solution, observe after 10 minutes and formed precipitation.Removal of solvent under reduced pressure then.

(B) in Rotary Evaporators, fill argon; (7-dimethylaminomethyl-6-formyl-dimethylamino-8-hydroxyl-2; 3-dimethyl-imidazo [1,2-a] pyridine-1- iodide) vacuum drying, and be dissolved in the dry DMF (1.1L) that is heated to 50 ℃ in advance.Obtained almost clear solutions, with its with potassium carbonate (30.4g, 220mmol) and 1-(1-phenyl-vinyl)-pyrrolidine (CAS3433-56-5,82.5g, purity: 90 weight-%, 428mmol) processing.In pre-warmed oil bath, this brown solution in 50 ℃ of stirrings 30 minutes, is poured on the mixture that is stirring of ammonium chloride (130g), water (200ml), ice (300g) and dichloromethane (600ml) then.Continue to stir a few minutes, pH value is adjusted to pH=8 by adding 6N hydrochloric acid.Separate each mutually also with dichloromethane (3 * 100ml) aqueous phase extracted.(dried over sodium sulfate is used in 2 * 100ml) washings, and concentrating under reduced pressure (removing DMF under 60 temperature) with the organic facies water that merges.Obtained dark-brown oily residue (80g), with its vacuum drying.

(C) with residue (crude product of this title compound) by come purification [500g, eluant: ethyl acetate (removing the 1-Phenylethanone. that the cracking by excessive enamine forms) is ethyl acetate/methanol=8: 2 (v/v) then] via filtered through silica gel.(crude product of this title compound of 60g, HPLC-purity: 88.08%), with its vacuum drying, be dissolved in the methanol (200ml), (25.5g 220mmol) handles with fumaric acid to isolate the rufous solid.This brown suspension in 40 ℃ of stirrings 20 minutes, has been obtained settled solution.This solution decompression is concentrated until forming heavy-gravity suspension.Add acetone (120ml), this mixture is concentrated once more until forming the thickness suspension.This serosity is diluted with acetone (150ml), in 40 ℃ (30 minutes), room temperature (19 hours) and 0 ℃ (2 hours) stirring.By removing by filter formed precipitation, with acetone (20ml) and ether (50ml) washing, and vacuum drying.Obtained colorless solid (51g, 49% yield, fusing point: 196-198 ℃), by ¹H-NMR spectrum shows that it is this title compound and the salt of fumaric acid with 1: 1 mol ratio formation.

(D) salt that this title compound and fumaric acid are formed (50g, 104mmol) be added in batches sodium bicarbonate (42g, 500mmol), in the mixture of water (400ml) and dichloromethane (400ml).This biphase mixture was stirred 5 minutes.Separate each phase, and with dichloromethane (2 * 50ml) aqueous phase extracted.(dried over sodium sulfate is used in 2 * 100ml) washings, and concentrating under reduced pressure with the organic facies water.Having obtained colourless foam shape solid, is this title compound (37.7g, 99% yield, 49% total recovery) through identifying it. ¹H-NMR spectrum shows that this sample is pure, and shows 99.07% HPLC purity (RT=9.4 minute).With its vacuum drying (five phosphorous oxide, 1 day).

Fusing point: 115-117 ℃

¹H-NMR(CDCl ₃，200MHz)：δ＝2.32，2.37(2s，6H)，2.95(s)，3.05(bs)，3.14(s，∑8H)，3.42(m _c，2H)，7.29(s，1H)，7.47(m _c，3H)，8.00(m _c，2H).

Xxxvii.8-hydroxyl-2,3-dimethyl-7-[3-(2-aminomethyl phenyl)-3-oxo-propyl group]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

(A) in the flame-dried flask of filling argon, with pure 8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (15.0g, 64mmol) the suspension iodate N in anhydrous methylene chloride (500ml), (11.9g 64mmol) handles N-dimethylated methylene base imonium.With this reactant mixture in stirring at room 1.5 hours.Removal of solvent under reduced pressure has been separated to yellow solid.

The 7-dimethylaminomethyl that (B) will make in (A)-6-formyl-dimethylamino-8-hydroxyl-2, the crude product of 3-dimethyl-imidazo [1,2-a] pyridine-1- iodide is dissolved in the dry DMF (300ml).Add potassium carbonate (8.9g, 64mmol) after, obtained settled solution, with it with 1-[1-(2-aminomethyl phenyl)-vinyl]-(CAS 156004-72-7,36.5g 195mmol) handle pyrrolidine.In pre-warmed oil bath, this brown solution is used in 50 ℃ stirred 4 hours, pour into then on the mixture of frozen water (400ml) and dichloromethane (400ml).By adding 6N hydrochloric acid pH value is adjusted to pH=7.Separate each phase, and with dichloromethane (2 * 200ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure (under 60 ℃ temperature, removing DMF).Obtained dark-brown oily residue (45g).(C) with residue (crude product of this title compound) by come purification [600g, eluant: ethyl acetate (removing the o-methyl-benzene ethyl ketone that the cracking by excessive enamine forms), ethyl acetate/methanol=8: 2 (v/v) then] via filtered through silica gel.Isolate two batches of these title compounds (the brown cystose solid of 8.65g brown oil/19.81g), with its independent purification.With substance dissolves in methanol (100ml/200ml), 50 ℃ of stirrings until obtaining settled solution (about 10 minutes).(94.0mmol) solution in methanol (100ml/200ml) continues to stir 10 minutes for 4.76g, 41.0mol/10.90g to add fumaric acid.This solution decompression is concentrated, acetone (50ml/100ml) is added in the brown crystalline residue, with this mixture stirring at room 19 hours.By removing by filter formed precipitation, with ether (20ml/50ml) washing, and vacuum drying.Obtained ecru solid (6.10g/19.87g, the yield of 51+29%), by ¹H-NMR spectrum shows that it is this title compound and the salt of fumaric acid with 1: 2 mol ratio formation.

(D) (6.10,18.8mol/19.87g 32.5mmol) is added in the mixture of saturated sodium bicarbonate solution (100ml/200ml) and dichloromethane (100ml/200ml) salt that this title compound and fumaric acid are formed in batches.Separate each phase, and with dichloromethane (50ml/100ml) aqueous phase extracted.With the organic facies dried over sodium sulfate, and concentrating under reduced pressure.Isolate the cystose solid, it is suspended in the ether (50ml/100ml).After 30 minutes/15 minutes, by filtering to isolate precipitation, with ether (20ml/50ml) washing, and vacuum drying.2 batches of these title compounds have been separated to: 2.63g colorless solid [11% yield, HPLC purity: 97.3% (RT=10.7 minute)] and 10.4g colorless solid [43% yield, HPLC purity: 99.6% (RT=10.7 minute)].

Fusing point: 179-180 ℃/182-183 ℃ (ether)

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.32，2.35，2.41(3s，9H)，2.79，2.88(m _c，s，5H)，3.01，3.08(s，m _c，5H)，5.45(bs)，7.37(m _c，3H)，7.71(m _c，2H).

Xxxviii.7-[3-(2-fluorophenyl)-3-oxo-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

(A) in the flame-dried flask of filling argon, with pure 8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (25.0g, 107mmol) the suspension iodate N in anhydrous methylene chloride (1L), (19.8g 107mmol) handles N-dimethylated methylene base imonium.With this reactant mixture stirring at room 1.5 hours.When beginning, obtained settled solution, observe after 30 minutes and formed precipitation.Removal of solvent under reduced pressure then.

(B) in Rotary Evaporators, fill argon; light yellow solid (7-dimethylaminomethyl-6-formyl-dimethylamino-8-hydroxyl-2; 3-dimethyl-imidazo [1,2-a] pyridine-1- iodide) is dissolved in the dry DMF (600ml) that is heated to 50 ℃ in advance.Add potassium carbonate (5.9g, 107mmol) after, obtained settled solution, with it with 1-[1-(2-fluorophenyl)-vinyl]-pyrrolidine (CAS 237436-15-6,53.2g, 278mmol, purity: 80mol-%) handle.In pre-warmed oil bath, this brown solution was stirred 2 hours at 50 ℃, pour into then on the mixture of frozen water (600ml) and dichloromethane (500ml).By adding 6N hydrochloric acid pH value is adjusted to pH=7.Separate each phase, and with dichloromethane (2 * 300ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure (under 60 ℃ temperature, removing DMF).Obtained dark-brown oily residue (72g).

(C) with residue (crude product of this title compound) by come purification [800g, eluant: ethyl acetate (removing the o-fluoro acetophenone that the cracking by excessive enamine forms), ethyl acetate/methanol=8: 2 (v/v) then] via filtered through silica gel.Be separated to brown solid (crude product of this title compound of 39g), it has been dissolved in the methanol (800ml), with fumaric acid (21.3g, 183mmol) solution-treated in methanol (500ml).This brown solution was stirred 10 minutes in 50 ℃.With solvent evaporation, acetone (120ml) is added in this brown solid residue, this mixture stirring at room 19 hours, was stirred 2 hours at 0 ℃.By filtering to isolate precipitation, with ether (50ml) washing, and vacuum drying.Obtained colorless solid (45.9g, 59% yield), by ¹H-NMR spectrum shows that it is this title compound and the salt of fumaric acid with 1: 3 mol ratio formation.

(D) (45.9g 63mmol) is added in the mixture that is stirring of dichloromethane (500ml) and saturated sodium bicarbonate solution (400ml) salt that this title compound and fumaric acid are formed in batches.This biphase mixture is stirred until solid dissolving (about 15 minutes) fully.Separate each phase, with dichloromethane (100ml) aqueous phase extracted.With the organic facies dried over sodium sulfate, and concentrating under reduced pressure.Isolated green foam shape solid (23g), it has been suspended in the ether (200ml).This suspension after 2 hours, is isolated precipitation and vacuum drying by filtering in stirring at room.Be separated to this title compound, be ecru solid (21.0g, 51% total recovery). ¹H-NMR spectrum shows that this sample is pure, and shows 98.12% HPLC purity (RT=9.4 minute).

Fusing point: 196 ℃

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.32，2.35(2s，6H)，2.89(bm _c，s，5H)，2.99(s，3H)，3.18(bm _c，2H)，5.48(bs)，7.33(m _c，2H)，7.65，7.69(m _c，s，2H)，7.81(dt，1H).

Xxxix.7-[3-(4-fluorophenyl)-3-oxo-propyl group]-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

(A) in the flame-dried flask of filling argon, with pure 8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (10.0g, 43mmol) the suspension N in anhydrous methylene chloride (500ml), (7.9g 43mmol) handles N-dimethylated methylene base imonium.With this reactant mixture stirring at room 1.5 hours.When beginning, obtained settled solution, observe after 30 minutes and formed precipitation.Removal of solvent under reduced pressure then.

(B) in Rotary Evaporators, fill argon; light yellow solid (7-dimethylaminomethyl-6-formyl-dimethylamino-8-hydroxyl-2; 3-dimethyl-imidazo [1,2-a] pyridine-1- iodide) is dissolved in the dry DMF (300ml) that is heated to 50 ℃ in advance.Add potassium carbonate (5.9g, 43mmol) after, obtained settled solution, with it with 1-[1-(4-fluorophenyl)-vinyl]-(CAS 237436-54-3,18.9g 99mmol) handle pyrrolidine.In pre-warmed oil bath, this brown solution was stirred 2 hours at 50 ℃, pour into then on the mixture of frozen water (300ml) and dichloromethane (300ml).By adding 6N hydrochloric acid pH value is adjusted to pH=7.Separate each phase, and with dichloromethane (2 * 200ml) aqueous phase extracted.With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure (under 60 ℃ temperature, removing DMF).Obtained dark-brown oily residue (28.8g).

(C) with residue (crude product of this title compound) by come purification [600g, eluant: ethyl acetate (remove cracking by excessive enamine form to fluoro acetophenone), ethyl acetate/methanol=7: 3 (v/v) then] via filtered through silica gel.Isolate brown solid (crude product of this title compound of 15.2g), it is dissolved in the methanol (400ml), (8.3g 72mmol) handles with fumaric acid.This brown suspension was stirred 15 minutes at 50 ℃, add methanol (400ml) again.Continuation was stirred 30 minutes at 50 ℃, had obtained settled solution.With solvent evaporation, acetone (80ml) is added in this brown solid residue, this mixture stirring at room 19 hours, was stirred 2 hours at 0 ℃.By filtering to isolate precipitation, with ether (30ml) washing, and vacuum drying.Obtained colorless solid (16.2g, 52% yield), shown that by 1H-NMR spectrum it is this title compound and the salt of fumaric acid with 1: 3 mol ratio formation.

(D) salt that this title compound and fumaric acid are formed (16.2g, 22mmol) mixture process of usefulness dichloromethane (200ml) and saturated sodium bicarbonate solution (200ml).This biphase mixture is stirred until solid dissolving (about 15 minutes) fully.Separate each phase, with dichloromethane (2 * 30ml) aqueous phase extracted.With the organic facies dried over sodium sulfate, and concentrating under reduced pressure.Isolated ecru cystose solid (8.4g), it has been suspended in the ether (100ml).This suspension after 1 hour, is isolated precipitation and vacuum drying by filtering in stirring at room.Be separated to this title compound, be ecru solid (7.53g, 46% total recovery). ¹H-NMR spectrum shows that this sample is pure, and shows 97.83% HPLC purity (RT=9.9 minute).

Fusing point: 221 ℃

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.32，2.35(2s，6H)，2.85，2.88(m _c，s，5H)，3.00(s，3H)，3.19(t，2H)，6.42(bs，1H)，7.34(t，2H)，7.70(s，1H)，8.05(q，2H).

Xi.8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-thiophene-2-base-propyl group)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

(A) 7-dimethylaminomethyl-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide can be as mentioned above by with 8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide and iodate N, N-dimethylated methylene base imonium reacts in dichloromethane and makes, and just handles this reactant mixture with saturated sodium bicarbonate solution, rather than be evaporated to dried.

(A) with 7-dimethylaminomethyl-8-hydroxyl-2, (18.8g 65mmol) is dissolved in the dry DMF (400ml) crude product of 3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide.Add potassium carbonate (8.9g, 64mmol) after, obtained settled solution; with it with 1-[1-thiophene-2-base-vinyl]-pyrrolidine (make by the condensation of 2-acetyl thiophene and pyrrolidine by the titanium tetrachloride mediation, referring to J.Org.Chem.1967,32; 213-214,27.1g, 151mmol).In pre-warmed oil bath, this biphase mixture was stirred 4 hours at 50 ℃, pour into then on the mixture of frozen water (500ml) and dichloromethane (400ml).By adding 6N hydrochloric acid pH value is adjusted to pH=7.Separate each phase, and with dichloromethane (3 * 200ml) aqueous phase extracted.With organic facies water (200ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure (under 60 ℃ temperature, removing DMF).Obtained (30g) oily residue.

(B) with residue (crude product of this title compound) by come purification [600g, eluant: ethyl acetate (removing the 2-acetyl thiophene that the cracking owing to excessive enamine forms), ethyl acetate/methanol=8: 2 (v/v) then] via filtered through silica gel.Isolated light brown solid (crude product of this title compound of 14.5g), it has been dissolved in the hot methanol (300ml).After 10 minutes, add fumaric acid (8.2g, 70mmol) solution in methanol (200ml).Continuation was stirred 10 minutes at 50 ℃, with solvent evaporation.Solid residue is suspended in the acetone (100ml), with this mixture stirring at room 17 hours.By filtering to isolate precipitation, with ether (30ml) washing, and vacuum drying.Obtained colorless solid (18.7g, 53% yield), by ¹H-NMR spectrum shows that it is this title compound and the salt of fumaric acid with 1: 1.5 mol ratio formation.

(C) (18.7g 34mmol) is added in the mixture of dichloromethane (250ml) and saturated sodium bicarbonate solution (100ml) salt that this title compound and fumaric acid are formed in batches.This biphase mixture is stirred until solid dissolving fully.Separate each phase, and with dichloromethane (50ml) aqueous phase extracted.With the organic facies dried over sodium sulfate, and concentrating under reduced pressure.Isolate light brown solid (11g), it is suspended in the ether (60ml).This suspension after stirring at room 2 hours, is come precipitation separation by filtration, and vacuum drying.Be separated to this title compound, be ecru solid (10.7g, 45% total recovery). ¹H-NMR spectrum shows that this sample is pure, and shows 99.04% HPLC purity (RT=8.3 minute).Fusing point: 234 ℃ (ether)

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.32，2.36(2s，6H)，2.81，2.89(m _c，s，5H)，3.01(s，3H)，3.14(t，2H)，5.85(bs)，7.24(dd，1H)，7.71(s，1H)，7.93(dd，1H)，8.00(dd，1H).

Xli.8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-Ethyl formate

(A) in the flame-dried flask of filling argon, with pure 8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-6-Ethyl formate (17.0g, 73mmol) the suspension N in anhydrous methylene chloride (550ml), (13.5g 73mmol) handles N-dimethylated methylene base imonium.With this reactant mixture stirring at room 70 minutes.When beginning, obtained settled solution, observe after 30 minutes and formed precipitation.Removal of solvent under reduced pressure then.

(B) in Rotary Evaporators, fill argon, with colorless solid (7-dimethylaminomethyl-6-ethoxy carbonyl-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-1- iodide) is dissolved in the dry DMF (350ml) that is heated to 50 ℃ in advance.Add gradually potassium carbonate (10.0g, 72mmol) and 1-(1-phenyl-vinyl)-pyrrolidine (CAS 3433-56-5,28.0g, purity: 90 weight-%, 145mmol) after, obtained almost clear solutions.In pre-warmed oil bath, this brown solution was stirred 90 minutes at 50 ℃, pour into then on the mixture of frozen water (200ml) and dichloromethane (300ml).By adding 6N hydrochloric acid pH value is adjusted to pH=7.Separate each phase, and with dichloromethane (3 * 40ml) aqueous phase extracted.(dried over sodium sulfate is used in 2 * 50ml) washings, and concentrating under reduced pressure (removing DMF under 70 ℃ temperature) with the organic facies water that merges.Obtained dark-brown oily residue (40g).

(C) residue (crude product of this title compound) is by coming purification [400g, eluant: ethyl acetate (removing the 1-Phenylethanone. that the cracking by excessive enamine forms), ethyl acetate/methanol=8: 2 (v/v) then] via filtered through silica gel.(crude product of this title compound of 31g, HPLC-purity: 74.05%), with its vacuum drying, be dissolved in the methanol (300ml), (16.0g 138mmol) handles with fumaric acid to have isolated brown solid.This brown suspension 40 ℃ of stirrings, has been obtained settled solution gradually, and it is evaporated to volume is 20ml.Add acetone (200ml), it is 20ml that this mixture is concentrated into volume once more.This serosity with acetone (120ml) dilution, is stirred in room temperature (19 hours) and 0 ℃ (2 hours), by filtering to isolate precipitation, with acetone (20ml) and ether (25ml) washing, and vacuum drying.Obtained colorless solid (20.0g, 65% yield, fusing point: 192-194 ℃, HPLC-purity: 93.92%), by ¹H-NMR spectrum shows that it is this title compound and the salt of fumaric acid with 2: 1 mol ratio formation.

(D) (19.5g, 46mmol) be added to water (200ml), sodium bicarbonate (20.0g is 238mmol) and in the mixture of dichloromethane (250ml) in batches for the salt that this title compound and fumaric acid are formed.This biphase mixture was stirred 5 minutes.Separate each phase, and with dichloromethane (2 * 20ml) aqueous phase extracted.(dried over sodium sulfate is used in 2 * 30ml) washings, and concentrating under reduced pressure with the organic facies water.Isolate colorless solid, through determining that it is this title compound (16.5g, 98% yield, 64% a total recovery).Sample (HPLC purity: 94.26%) contain unconverted raw material, it is further purified [400g silica gel, eluant: methylene chloride=100: 2 (v/v)] by flash chromatography.Obtained this title compound (14.5g, 55% yield), be almost colourless solid, it shows 98.33% HPLC purity (RT=14.1 minute).

Fusing point: 172-174 ℃.

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.29(t，3H)，2.34，2.41(2s，6H)，3.23(s，4H)，4.29(q，2H)，6.30(bs，1H)，7.51(t，2H)，7.64(t，1H)，7.98(d，2H)，8.19(s，1H).

Xiii.9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-Ethyl formate also

With 2,2-dimethoxy propane (8.6g, 10.1ml, 83mmol) be added to 8-hydroxyl-2, (2.00g is 5.5mmol) in the solution in anhydrous methylene chloride (25ml) for 3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-Ethyl formate.Add lentamente methanesulfonic acid (0.68g, 0.46ml, 7.1mmol) after, obtained dark-brown solution, it was refluxed 6 hours.With this reactant mixture cooling, pour in the mixture that is stirring of saturated sodium bicarbonate solution (25ml) and dichloromethane (20ml).This biphase mixture is stirred a few minutes, and separate each phase.With dichloromethane (2 * 15ml) aqueous phase extracted.With organic facies water (20ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure.Brown residue (3g) is handled with ether (15ml), the gained serosity was stirred 15 minutes.By filtering precipitation separation, with ether washing (5ml), and vacuum drying.Yield with 88% has obtained this title compound (1.85g colorless solid).

Fusing point: 184-186 ℃

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.35(t，3H)，1.90(m _c，1H)，2.34，2.37，2.43(s，m _c，s，7H)，2.99，3.12(s，m _c，5H)，4.33(q，2H)，7.49(m _c，3H)，7.63(m _c，2H)，8.36(s，1H).

Xliii.9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid also

To 9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-(1.80g 4.7mmol) adds potassium hydroxide aqueous solution (0.56g in the suspension in methanol (40ml) to imidazo [1,2-a] pyridine-6-Ethyl formate, 10.0mmol, the solution in 5ml water).The gained red suspension is heated to 55 ℃.After 30 minutes, obtained settled solution, it has been kept 90 minutes at 55 ℃.With this reactant mixture cooling, and concentrating under reduced pressure.Wet residue is dissolved in the water (40ml), 2N hydrochloric acid is added in this solution that is stirring until pH value 2.Continuation is stirring at room 1 hour, by removing by filter the precipitation that has formed.With filter cake water (showing pH neutral) and acetone (5ml) washing until filtrate, and vacuum drying.Yield with 97% has been separated to this title compound (1.6g anhydrous solid).

Fusing point: 240-242 ℃

¹H-NMR (dmso-d ₆+ micro-MeOD, 200MHz): δ=1.99 (m _c, 1H), 2.51 (m _c), 3.06 (s, 3H), 3.23 (m _c, 2H), 7.52 (m _c, 3H), 7.74 (m _c, 2H), 8.68 (s, 1H).

Xliv. (9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-pyrrolidine-1-base ketone

In the flask of filling argon, with 9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid (2.00g also, 5.7mmol) (2.10g 6.5mmol) handles with TBTU for suspension in anhydrous methylene chloride (35ml).

With this reaction mixture refluxed 2 hours, allow it be cooled to room temperature then.Add pyrrolidine (0.43g, 0.50ml, 6.0mmol) after, obtained yellow solution, with it stirring at room 1 hour.This reactant mixture is poured in the frozen water (30ml), by adding saturated sodium bicarbonate solution this biphase mixture that is stirring neutralization.Separate each phase, with dichloromethane (2 * 10ml) aqueous phase extracted.With organic facies water (20ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure.Residue (4g yellow oil) is passed through purified by flash chromatography [90g silica gel, eluant: methylene chloride=100: 2 (v/v)].Be separated to cystose solid (1.9g, 83% yield), its be this title compound (67mol-%), benzotriazole-1-alcohol (22mol-%) and tetramethylurea (mixture of 11 weight-%) [by ¹H-NMR is spectrometric].

¹H-NMR (dmso-d ₆, 200MHz): δ=1.87,2.07 (2m _c, 5H), 2.36,2.42 (2s, 6H), 2.55 (m _c), 2.69 (tetramethylureas), 2.86,3.02 (m _c, s, 4H), 3.26 (m _c), 3.50 (t, 2H), 7.48 (m _c, this title compound of 3H[], 2H[benzotriazole-1-alcohol]), 7.64,7.72 (2m _c, this title compound of 2H[], 1H[benzotriazole-1-alcohol]), 7.98 (d, 1H[benzotriazole-1-alcohol]), 8.11 (s, 1H).

Xlv.[8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-yl]-pyrrolidine-1-base ketone

With (9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-yl)-pyrrolidine-1-base ketone (1.80g, deriving from the crude product of experiment xliv) solution in THF (25ml) handles with 1N hydrochloric acid (10ml), 50 ℃ of heating 5 hours.Allow this reactant mixture be cooled to room temperature, pour in the mixture of frozen water (25ml) and dichloromethane (30ml), neutralize by adding the 2N sodium hydroxide solution.Separate each phase, (2 * 15ml) extract with dichloromethane with water.Wash the organic facies that merges with water (20ml), use dried over sodium sulfate, and vacuum concentration.With this title compound (1.2g, HPLC purity: 98.42%) be further purified [50g silica gel, eluant: ethyl acetate/methanol=10: 1 (v/v)] by flash chromatography.Being separated to colorless solid, with its vacuum drying, is pure this title compound (1.03g, 46% total recovery) through evaluation, HPLC purity: 99.55% (RT=10.9 minute).

Fusing point: 257-258 ℃

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.84(m _c，4H)，2.32，2.36(2s，6H)，2.87(m _c，2H)，3.24(m _c，4H)，3.46(m _c，2H)，6.85(bs，1H)，7.52(t，2H)，7.64(t，1H)，7.77(s，1H)，7.96(d，2H).

Xivi.9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea also

In the flask of filling argon, with 9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid (embodiment xliii, 2.00g, 5.7mmol) (2.10g 6.5mmol) handles with TBTU for suspension in anhydrous methylene chloride (35ml).With this reaction mixture refluxed 2 hours, allow it be cooled to room temperature then.Add gradually methyl amine (solution of 0.80ml 8M in ethanol, 6.4mmol) after, obtained yellow solution, with it stirring at room 1 hour.This reactant mixture is poured in the mixture of frozen water (30ml) and dichloromethane (10ml), by adding the biphase mixture that saturated sodium bicarbonate solution neutralizes and stirring.Continue to stir a few minutes, separate each phase, (2 * 10ml) extract with dichloromethane with water.Wash the organic facies that merges with water (20ml), use dried over sodium sulfate, and concentrating under reduced pressure.Residue (5g solid) is passed through purified by flash chromatography [100g silica gel, eluant: methylene chloride=100: 2 (v/v)].Be separated to colourless foam shape solid (2.2g), its be this title compound (53mol-%), benzotriazole-1-alcohol (39mol-%) and tetramethylurea (8mol-%) mixture [by ¹H-NMR is spectrometric].

¹H-NMR (dmso-d ₆, 200MHz): δ=1.92 (m _c, 1H), 2.39,2.45 (2s, m _c, 7H), 2.69 (tetramethylureas), 2.80 (d, m _c, 4H), 3.03,3.05 (s, m _c, 4H), 7.48 (m _c, this title compound of 3H[], 2H[benzotriazole-1-alcohol]), 7.67,7.72 (2m _c, this title compound of 2H[], 1H[benzotriazole-1-alcohol]), 7.99 (d, 1H[benzotriazole-1-alcohol]), 8.21 (s, 1H), 8.47 (bq, 1H).

Xlvii.8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea

With 9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] solution of pyridine-6-formic acid methyl nitrosourea (2.10g derives from the crude product of embodiment xivi) in THF (25ml) handles with 1N hydrochloric acid (10ml), 50 ℃ of heating 7 hours.This reactant mixture stirring at room 18 hours, is neutralized by adding saturated sodium bicarbonate solution then.Obtained yellow suspension, with it stirring at room 1 hour.By filtering to isolate precipitation, water (20ml) washing, and vacuum drying.Total recovery with 73% has been separated to this pure title compound (1.45g yellow solid), HPLC purity: 99.57% (RT=8.8 minute).

Fusing point: 284-286 ℃ (water)

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.32，2.38(2s，6H)，2.76(d，3H)，2.98(m _c，2H)，3.25(m _c，2H)，5.95(bs，1H)，7.52(t，2H)，7.64(t，1H)，7.82(s，1H)，7.98(d，2H)，8.34(bq，1H).

Xlviii. (9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-yl also)-methanol

In the flame-dried flask of filling argon, with 9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans is [2,3-c]-imidazo [1,2-a] pyridine-6-Ethyl formate (embodiment xlii also, 3.80g, 10.0mmol) be suspended among the anhydrous THF (70ml).Room temperature with 30 minutes with a small amount of mode repeatedly add lithium aluminium hydride (1.0g, 26mmol).Continue to stir 30 minutes in room temperature, this reactant mixture is poured into lentamente in the mixture of saturated ammonium chloride solution (30ml) and dichloromethane (150ml).Separate each phase, with dichloromethane (4 * 15ml) aqueous phase extracted.(dried over sodium sulfate is used in 2 * 20ml) washings, and concentrating under reduced pressure with the organic facies water that merges.With residue 2.9g yellow solid vacuum drying, be pure this title compound (86% yield) through identifying it.

Fusing point: 257-258 ℃

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.91(m _c，1H)，2.31，2.35，2.37(s，m _c，s，7H)，2.70(m _c，1H)，2.86(m _c，1H)，2.98(s，3H)，4.53(s，2H)，5.19(bs，1H)，7.48(m _c，3H)，7.63(m _c，2H)，7.75(s，1H).

Xlix.6-chloromethyl-9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine also

With (9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine-6-yl)-methanol (2.20g, 6.5mmol) suspension in anhydrous methylene chloride (80ml) is cooled to 0 ℃, adds thionyl chloride (0.59ml lentamente, 0.96g, 8.1mmol).Obtained yellow solution, it was stirred 1 hour at 0 ℃, poured into then on the saturated sodium bicarbonate solution (20ml).This aqueous mixture stirring is stopped until gas release, and separate each phase.With dichloromethane (2 * 10ml) aqueous phase extracted.The organic facies that merges is washed with saturated ammonium chloride solution (20ml) and water (30ml), use dried over sodium sulfate, solvent removed under reduced pressure.Be separated to colourless foam shape solid, with its vacuum drying.This title compound (2.3g, 99% yield) need not be further purified and be directly used in next step.

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.93(m _c，1H)，2.31，2.38，2.41(2s，m _c，7H)，2.82(m _c，1H)，2.99，3.02(s，m _c，4H)，4.89(dd，2H)，7.47(m _c，3H)，7.63(m _c，2H)，8.10(s，1H).

L.9-methoxyl group-6-methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine also

With 6-chloromethyl-9-methoxyl group-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] pyridine (derive from the crude product of embodiment xlix, 2.20g 6.2mmol) is dissolved in the absolute methanol (20ml).Add Feldalat NM (solution: the solution of 30 weight-% in methanol, 3.0ml, 17mmol) after, obtained yellow suspension, be heated to 50 ℃.Formed yellow solution in 90 minutes, it is concentrated into volume is 10ml, pours in the mixture of saturated ammonium chloride solution (15ml) and dichloromethane (20ml).By adding 2N hydrochloric acid it being adjusted to pH value is 7, and separates each phase.With dichloromethane (2 * 8ml) aqueous phase extracted.With organic facies water (20ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure.Be separated to the oily residue, with its vacuum drying.This title compound (2.1g cystose solid, 98% yield) need not be further purified and be directly used in next step.

¹H-NMR(dmso-d ₆，400MHz)：δ＝1.92(m _c，1H)，2.30，2.37，2.37(2s，m _c，7H)，2.70(m _c，1H)，2.90(m _c，1H)，2.98(s，3H)，3.33(s)，4.43(s，2H)，7.46(m _c，3H)，7.62(m _c，2H)，7.82(s，1H).

Li.3-(8-hydroxyl-6-methoxy-2,3-dimethyl-imidazo [1,2-a] pyridine-7-yl)-1-phenyl-third-1-ketone

With 9-methoxyl group-6-methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans also [2,3-c]-imidazo [1,2-a] and pyridine (derive from the crude product of EXAMPLE l, 2.00g, 5.7mmol) solution in THF (40ml) is handled with 2N hydrochloric acid (15ml).This yellow solution stirring at room 19 hours, 50 ℃ of heating 2 hours, is poured on the mixture of water (50ml) and dichloromethane (100ml).Be adjusted to pH neutral by adding the 2N sodium hydroxide solution, and separate each phase.With dichloromethane (2 * 15ml) aqueous phase extracted.With organic facies water (30ml) washing that merges, use dried over sodium sulfate, and be evaporated to dried.Solid residue (1.9g) is suspended in the acetone (2ml).After 30 minutes, by filtering to isolate precipitation, with cold acetone (2ml) and ether (10ml) washing, and vacuum drying.Yield with 63% has been separated to this pure title compound (1.20g light yellow solid), HPLC purity: 98.20% (RT=12.1 minute).

Fusing point: 167-168 ℃ (acetone)

¹H-NMR(dmso-d ₆，200MHz)：δ＝2.30，2.35(2s，6H)，2.97(t，2H)，3.25，3.28(m _c，s，5H)，4.47(s，2H)，7.11(bs)，7.58(m _c，3H)，7.71(s，1H)，7.98(m _c，2H).

The asymmetric reduction of prochiral ketones:

Lii. (3S)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

In the flame-dried flask of filling argon, with ketone 8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxvi, 5.00g, 13.7mmol) be suspended in the anhydrous isopropyl alcohol (400ml) of using argon-degassed.(1.85g 15.1mmol) afterwards, has obtained yellow solution, and it is used hydrogenation catalyst RuCl to add potassium tert-butoxide ₂[(R)-BINAP] [(R)-and DAIPEN] (CAS 329735-86-6, catalyst is available from Strem Chemicals) (125mg, 0.11mmol, S/C=125: 1) handle.This reddish yellow solution stirring at room 20 minutes, is transferred under inert conditions in the 1L autoclave that is equipped with the glass inlay.To this reactant mixture with pressurized with hydrogen (40 crust), stirring at room 22 hours.It is 80ml that this yellow-brownish solution is concentrated into volume.Add frozen water (80ml) and dichloromethane (130ml), it is adjusted to pH neutral by adding 2N hydrochloric acid.Separate each phase, with dichloromethane (3 * 15ml) aqueous phase extracted.With organic facies water (30ml) washing that merges, with dried over sodium sulfate and concentrating under reduced pressure.Residue green solid (8g) is passed through purified by flash chromatography [80g silica gel, eluant: methylene chloride=20: 1 (v/v)].With the suspension of this title compound in acetone (30ml) of purification in stirring at room a few minutes.By filtering precipitation separation, with acetone (5ml) and ether (15ml) washing, vacuum drying.Having obtained colorless solid (4.40g, 87% yield), is this title compound (optical purity: 95.5%ee) through identifying it.

Fusing point: 185-187 ℃ (acetone).

Measure optical purity by CE: RT[(3S)-enantiomer]=18.5 minutes/97.7 areas-%;

RT[(3R)-enantiomer]=19.0 minutes/2.3 areas-%; 95.5%ee (A).

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.81(m _c，2H)，2.30，2.33(2s，6H)，2.50(bm _c)，2.78，2.91(2s，6H)，4.49(t，1H)，5.43(bs)，7.25(m _c，5H)，7.59(s，1H).

Iiii. (3R)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

In the flame-dried flask of filling argon, with ketone 8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxxvi, 10.00g, 27.4mmol) be suspended in the anhydrous isopropyl alcohol (400ml) of using argon-degassed.Add potassium tert-butoxide (3.70g, 30.2mmol) after, continue to stir until obtaining yellow solution (about 30 minutes).Add hydrogenation catalyst RuCl ₂[(S)-BINAP] [(S)-and DAIPEN] (CAS 212143-24-3, catalyst is available from Strem Chemicals) (240mg, 0.21mmol, S/C=130: 1).Gained reddish yellow solution stirring at room 15 minutes, is transferred under inert conditions in the 1L autoclave that is equipped with the glass inlay.To this reactant mixture with pressurized with hydrogen (40 crust), stirring at room 24 hours.It is 50ml that this brown solution is concentrated into volume.Pour in the cold mixt of saturated ammonium chloride solution (120ml) and dichloromethane (250ml).By adding 6N hydrochloric acid it is adjusted to pH neutral.Separate each phase, with dichloromethane (2 * 40ml) aqueous phase extracted.With organic facies water (30ml) washing that merges, with dried over sodium sulfate and concentrating under reduced pressure.Having obtained the light green color solid, with its vacuum drying, is this title compound (9.30g, 92% yield, optical purity: 85.8%ee) through identifying it.

Fusing point: 152-154 ℃

Measure optical purity by CE: RT[(3S)-enantiomer]=20.2 minutes/7.1 areas-%;

RT[(3R)-enantiomer]=20.5 minutes/92.9 areas-%; 85.8%ee (A).

Liv. (3R)-[8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-yl]-pyrrolidine-1-base ketone

In the flame-dried flask of filling argon, with ketone [8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-yl]-pyrrolidine-1-base ketone (embodiment xlv, 1.00g, 2.6mmol) be suspended in the anhydrous isopropyl alcohol (120ml) of using argon-degassed.Add potassium tert-butoxide (0.34g, 2.8mmol) after, obtained yellow solution, use hydrogenation catalyst RuCl ₂[(S)-BINAP] [(S)-and DAIPEN] (CAS 212143-24-3, catalyst is available from Strem Chemicals) (130mg, 0.12mmol, S/C=20: 1) handle.With the gained mixture stirring at room a few minutes until catalyst dissolving fully, under inert conditions, transfer in the 1L autoclave that is equipped with the glass inlay.To this reactant mixture with pressurized with hydrogen (40 crust), stirring at room 22 hours.It is 30ml that this green solution is concentrated into volume, pours on the mixture of frozen water (20ml) and dichloromethane (40ml).By adding 6N hydrochloric acid it is adjusted to pH neutral.Separate each phase, with dichloromethane (3 * 10ml) aqueous phase extracted.With organic facies water (20ml) washing that merges, use dried over sodium sulfate, and concentrating under reduced pressure.Green residue (1.8g) is passed through purified by flash chromatography [80g silica gel, eluant: methylene chloride=100: 3 (v/v)].With the suspension of this title compound in ether (10ml) of this purification in stirring at room a few minutes.By filtering precipitation separation, with ether (5ml) washing, and vacuum drying.Having obtained light green color solid (780mg, 78% yield), is this title compound (optical purity: 87.4%ee) through identifying it.

Fusing point: 252-254 ℃ (ether)

Measure optical purity by CE: RT[(3S)-enantiomer]=20.2 minutes/6.3 areas-%;

RT[(3R)-enantiomer]=20.4 minutes/93.7 areas-%; 87.4%ee (A).

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.77(m _c，6H)，2.30，2.33(2s，6H)，2.55(m _c)，3.13，3.34(2t，4H)，4.49(t，1H)，5.93(bs)，7.25(m _c，5H)，7.65(s，1H).

Iv. (3R)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea

In the flame-dried flask of filling argon, with ketone 8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-formic acid methyl nitrosourea (embodiment xlvii, 1.30g, 3.7mmol) be suspended in the anhydrous isopropyl alcohol (120ml) of using argon-degassed.Add potassium tert-butoxide (0.50g, 4.1mmol) after, obtained thin yellow suspension, stirring at room 30 minutes.Add the isopropyl alcohol (30ml) of the degassing again, this suspension is warm slightly.Add and use hydrogenation catalyst RuCl ₂[(S)-BINAP] [(S)-and DAIPEN] (CAS212143-24-3, catalyst is available from Strem Chemicals) (80mg, 0.07mmol, S/C=50: 1).With the gained mixture stirring at room 20 minutes until catalyst dissolving fully, under inert conditions, transfer in the 1L autoclave that is equipped with the glass inlay.To this reactant mixture with pressurized with hydrogen (40 crust), stirring at room 22 hours.It is 20ml that this green solution is concentrated into volume, pours in the mixture that is stirring of frozen water (25ml) and dichloromethane (50ml).By adding 6N hydrochloric acid it is adjusted to pH neutral.Separate each phase, and with dichloromethane (3 * 15ml) aqueous phase extracted.With organic facies (containing sedimentary the title compound) concentrating under reduced pressure that merges.Anhydrate in order to remove, with green residue coevaporation in the presence of dichloromethane (3 *).The crude product (1.3g) of this title compound is come purification by crystallization from methanol (75ml).With this suspension stirring at room 18 hours.Isolate precipitation by filtering, with acetone (10ml) and ether (20ml) washing, and vacuum drying.Having obtained colorless solid (1.05g, 80% yield), is this title compound (optical purity: 92.0%ee) through identifying it.

Fusing point: 250-252 ℃ (methanol)

Measure optical purity by CE: RT[(3S)-enantiomer]=19.2 minutes/4.0 areas-%;

RT[(3R)-enantiomer]=19.6 minutes/96.0 areas-%; 92.0%ee (A).

The asymmetric hydrogenation of prochiral olefin:

Ivi. (3R)-8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide

In the flame-dried flask of filling argon, add (R)-Alpine-boramine ^TM(CAS 67826-92-0,1.50g, 3.6mmol).After adding anhydrous THF (8ml), obtained colourless solution, (0.92ml, 1.03g 7.3mmol) handle with the boron trifluoride diethyl etherate compound with it.With this solution stirring at room 2 hours.Obtained colourless precipitation,, washed with cold THF (6ml, argon atmospher) by filtering to isolate precipitation.Merging filtrate [containing (-)-Dan Yisong pinanyl borine].Add (E)-8-hydroxyl-2 lentamente in room temperature, 3-dimethyl-7-(3-phenyl-pi-allyl)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment xxiii, 0.42g, 1.2mmol) suspension in anhydrous THF (15ml), obtained yellow solution.After 5 hours response time, (solution of 30 weight-% in water is on cold mixt 1.6ml) to pour this solution into potassium hydroxide aqueous solution (solution of 230mg in 1.6ml water), ethanol (4ml) and hydrogen peroxide.After 30 minutes, this reactant mixture is poured on saturated ammonium chloride solution (20ml) and the dichloromethane (40ml).Separate each phase, with dichloromethane (1 * 10ml) aqueous phase extracted.The organic facies that merges is washed with water, use dried over sodium sulfate, and concentrating under reduced pressure.Crude product (1.9g yellow oil) is passed through purified by flash chromatography [40g silica gel, eluant: dichloromethane (to remove isopinocampheol), methylene chloride=20: 1 (v/v) then].Corresponding level part is evaporated, obtained solid (320mg), it with acetone (1ml) washing, is separated by filtering, and vacuum drying.Yield with 50% has been separated to this title compound (0.22g colorless solid, optical purity: 27.8%ee).

Fusing point: 178-180 ℃ (acetone)

Measure optical purity by CE: RT[(3S)-enantiomer]=18.3 minutes/36.1 areas-%;

RT[(3R)-enantiomer]=18.6 minutes/63.9 areas-%; 27.8%ee (A).

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.81(m _c，2H)，2.30，2.33(2s，6H)，2.50(bm _c)，2.78，2.91(2s，6H)，4.49(t，1H)，5.69(bs)，7.25(m _c，5H)，7.59(s，1H).

IV. conformational analysis

The configuration of formula 1 and 2 chemical compounds is given and is based on J.A.Dale and H.S.Mosher at J.Am.Chem.Soc.1973, and 95, the method for describing among the 512-519.The following examples are for example understood this method in more detail, but are not limited thereto.The configuration of other formula 1 and 2 chemical compounds can be analyzed according to being similar to the method shown in the reaction scheme 8 equally.

Reaction scheme 8:

Well-known is that the configuration that is accompanied by of Mitsunobu reaction is changed (referring to for example O.Mit-sunobu Synthesis 1981,1; D.L.Hughes Org.Prep.Proc.Int.1996,28,127).Specifically, when adopting chirality secondary amine, S takes place in reactant _NConfiguration conversion (referring to for example N.L.Dirlam, B.S.Moore, F.J.Urban J.Org.Chem.1987,52,3587) takes place in 2 displacement reactions simultaneously.Therefore, (9S)-enantiomer (formula 1 chemical compound, embodiment 2) is derived from (3R)-8-hydroxyl-7-[3-hydroxyl-3-phenyl-propyl group]-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide.For 8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] configuration of mapping glycol of pyridine-6-formic acid dimethylformamide gives, will be by ketone 8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] hydrogenation [1.2 equivalent potassium tert-butoxides, the 2mol-%RuCl of pyridine-6-formic acid dimethylformamide ₂[(S)-BINAP] [(S, S)-DPEN], 45 crust hydrogen-pressure, isopropyl alcohol, 80 ℃, 18 hours, 82% yield] and the sample that the is rich in enantiomer tert-butyl group dimethyl chloride silane treated (reaction scheme 8) of acquisition.By gained silyl ether (3S)-and (3R)-8-(tert-butyl group-dimethyl silane oxygen base)-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide, formula 24 chemical compounds (R1 wherein, R2=CH ₃, R3=(CH ₃) ₂N-C (O), the Arom=phenyl), (7: 3 enantiomer (3R): HPLC (3S) ratio) separates the enantio-selectivity that has confirmed this catalytic hydrogenation.Handle the product of formula 24 with (S)-(+)-MTPACI, what obtained formula 25 removes acidylate imidazopyridine (R1, R2=CH ₃, R3=(CH ₃) ₂N-C (O), the Arom=phenyl).The phenolic ester basic capsule is taken off, obtained non-mapping Mosher ester (R1, the R2=CH of formula 26 with 7: 3 ratios ₃, R3=(CH ₃) ₂N-C (O), Arom=phenyl), described ratio is according to the result of the silyl ether enantiomer of formula 24 and definite.

Fig. 1

" shielding "

Mosher and partner thereof show that for this compounds, the conformation shown in Fig. 1 is a high-priority.In (the 3R)-diastereomer of formula 26 chemical compounds, the methoxy functional cumularsharolith is above the Arom group.The screen effect of aromatics electronics can cause, compares with (3S)-diastereomer, methoxyl group ¹The H-NMR signal moves to High-Field.At non-enantiomer mixture ¹In the H-NMR spectrum, observed the signal of methoxyl group at 3.43ppm (mainly)/3.52ppm (less important) respectively.Therefore, the catalytic hydrogenation under the condition of reporting in the above mainly provides (the 3R)-glycol of formula 23.After the Mitsunobu etherificate, be separated to the sample that is rich in enantiomer of (the 9S)-enantiomer of formula 1.

The experimental detail of conformational analysis

A.8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide; Make by asymmetric catalytic hydrogenation

With ketone 8-hydroxyl-2,3-dimethyl-7-(3-oxo-3-phenyl-propyl group)-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (2.00g, 5.5mmol), potassium tert-butoxide (0.74g, 6.6mmol) and hydrogenation catalyst RuCl ₂[(S)-and BINAP] [(S, S)-and DPEN] (CAS 329736-05-2, catalyst is available from Strem Chemicals or can be according to R.Noyori and T.Ohkuma at Angew.Chem.2001,113, the method of describing among the 40-75 makes, 110mg, 0.11mmol, S/C=60: 1) be dissolved in the anhydrous isopropyl alcohol (150ml) of using argon-degassed.Should transfer in the 300ml autoclave by uniform brown solution,, and be heated to 80 ℃ with pressurized with hydrogen (45 crust).This reactant mixture was kept 18 hours at 80 ℃, be cooled to room temperature, and concentrating under reduced pressure.Residue is dissolved in the water (50ml), the pH value of this solution is adjusted to 7.5 by adding 2N hydrochloric acid (2.4ml).With dichloromethane (3 * 100ml) aqueous phase extracted.Regulate pH value once more, extraction is repeated 2 times again.With the organic facies that merges with dried over sodium sulfate and concentrating under reduced pressure.The green brown solid of residue is passed through purified by flash chromatography [100g silica gel, eluant: methylene chloride=15: 1 (v/v)].Being separated to gray solid (1.64g, 82% yield), is pure glycol 8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2 through identifying it, 3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide.At chemical compound ¹Do not see any microchemistry impurity in the H-NMR spectrum.Because the hangover of strong peak, optical purity and the enantiomeric excess of directly measuring sample by chirality HPLC are impossible.

¹H-NMR(dmso-d ₆，200MHz)：δ＝1.81(m _c，2H)，2.30，2.33(2s，6H)，2.50(bm _c，2.78，2.91(2s，6H)，4.49(t，1H)，7.25(m _c，5H)，7.59(s，1H).

B.8-(tert-butyl group-dimethyl silane oxygen base)-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide; The mensuration of the enantiomeric excess that the asymmetric reduction by ketone obtains

In order to analyze, with glycol 8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (200mg, 0.54mmol, the asymmetric hydrogenation product of describing among the embodiment a) be dissolved in the dichloromethane (10ml).(110mg, 151 μ l are 1.09mmol) with tert-butyl group dimethyl chloride monosilane (179mg, 1.19mmol) solution in dichloromethane (5ml) to add triethylamine.With this reactant mixture reflux 5.25 hours, come stopped reaction by adding saturated ammonium chloride solution (10ml) then.Separate each phase, with water dichloromethane extraction water (2 * 10ml).With the organic facies dried over sodium sulfate that merges, and concentrating under reduced pressure.Obtained green grease (296mg), it has been passed through purified by flash chromatography (20g silica gel, eluant: ethyl acetate).Yield with 73% has been separated to this title compound (190mg).In colorless oil ¹Do not see any impurity in the H-NMR spectrum.Use following condition to come to measure enantiomeric excess: post: 2CHIRALPAK by chirality HPLC ^AD-H post 250 * 4.6mm, 5 μ m; Eluant: isopropanol/hexane=17: 83 (v/v), flow velocity: 1ml/ minute; Temperature; 35 ℃.((31.65 areas-%) are eluted with 9.97 minutes/10.60 minutes retention time respectively 68.35 areas-%) and (3S)-enantiomer (the 3R)-enantiomer of this title compound.Therefore, asymmetric catalytic hydrogenation carries out with 36.7%ee.

¹H-NMR(CDCl ₃，200MHz)：δ＝0.33，0.44(2s，6H)，1.02(s，9H)，2.00(m _c，2H)，2.33，2.37(2s，6H)，2.65(m _c，2H)，2.88，3.11(2s，6H)，4.58(dd，1H)，7.26m _c，5H)，7.38(s，1H).

C. (2R)-3,3,3-three fluoro-2-methoxyl group-2-phenyl-propanoic acid [3-(6-formyl-dimethylamino-8-hydroxyl-2,3-dimethyl-imidazo [1,2-a] pyridine-7-yl)-(1R, S)-1-phenyl-propyl diester; 8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2, the configuration of the enantiomer of 3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide is given

(A) in order to measure 8-hydroxyl-7-(3-hydroxyl-3-phenyl-propyl group)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (absolute configuration of a) (3S) of embodiment-and (3R)-enantiomer, (95mg 0.38mmol) is dissolved in pyridine (810 μ l) and the carbon tetrachloride (810 μ l) with (S)-(+)-MTPACI.Add silyl ether 8-(tert-butyl group-dimethyl silane oxygen base)-7-(3-hydroxyl-3-phenyl propyl)-2,3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide (embodiment b, 100mg, 0.21mmol containing proportional is two kinds of enantiomer of 7: 3) (3R)-and (the 3S)-solution of enantiomer in dichloromethane (500 μ l).With this reactant mixture stirring at room 6 hours, water (5ml) and chloroform (10ml) dilution then.Separate each phase, (2 * 10ml) extract with chloroform with water.Organic facies with saturated ammonium chloride solution (5ml) washing, is used dried over sodium sulfate, and concentrating under reduced pressure.With the crude product intensive drying, then by purified by flash chromatography (10g silica gel, eluant: ethyl acetate/petroleum ether=7: 3).Being separated to light yellow oil (50mg, 30% yield), is the non-enantiomer mixture of the diester of formula 25 through identifying it, R1 wherein, R2=CH ₃, R3=(CH ₃) ₂N-C (O), and Arom=phenyl.

¹H-NMR(CDCl ₃，200MHz)：δ＝2.00-2.60(bs)，2.34，2.37(2s，∑10H)，2.73(s，3H)，2.87，2.97(2s，∑3H)，3.44，3.48(2s，∑3H)，3.79，3.85(2s，∑3H)，5.61(bt，1H)，7.30(m _c，10H)，7.54(m _c，3H)，7.63(s，1H)，8.06(m _c，2H).

(B) incite somebody to action wherein R1, R2=CH ₃, R3=(CH ₃) ₂N-C (O), and the solution of non-enantiomer mixture in deuterochloroform of the diester of the formula 25 of Arom=phenyl left standstill 10 days in room temperature.Removal of solvent under reduced pressure has been separated to wherein R1, R2=CH with crude product by the yield of purified by flash chromatography [2 * 6g silica gel, eluant: methylene chloride=15: 1 (v/v)] with 72% ₃, R3=(CH ₃) ₂N-C (O), and the non-enantiomer mixture of the ester of the formula 26 of Arom=phenyl (22mg colourless foam shape thing).At this chemical compound ¹In the H-NMR spectrum, see two unlike signals of the methoxyl group of acyl moiety.With mainly/chemical displacement value of the corresponding signal of less important enantiomer is 3.43/3.52ppm.

¹H-NMR(dmso-d ₆，400MHz)：δ＝2.05(bs，1H)，2.17(bs，1H)，2.29，2.32(2s，6H)，2.48(bs)，2.71，2.75(2s，∑3H)，2.82，2.84(2s，∑3H)，3.43，3.52(2s，Σ3H)，5.98(m _c，1H)，7.41(m _c，10H)，7.61，7.62(2s，∑1H).

The method that is used for conformational analysis based on people such as Mosher (seeing above) proposition, the glycol 8-hydroxyl-7-that makes as mentioned above (3-hydroxyl-3-phenyl-propyl group)-2, the main enantiomer of 3-dimethyl-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide has (3R)-configuration.

Commercial practicality

Formula 1 chemical compound and salt thereof have useful pharmacological characteristics, and this makes it have commercial utilizability.Particularly they have significant stomachial secretion inhibitory action and excellent in homoiothermic animal, particularly people's gastrointestinal defencive function.The unique distinction of The compounds of this invention is the high selectivity that acts on, favourable acting duration, especially good enteral activity, no remarkable side effect and wide range of therapeutic scope.

" gastrointestinal protection " in this article refers to prevention and treatment gastrointestinal disease; especially gastroenteritis disease and infringement (gastric ulcer for example; peptic ulcer; comprise that peptic ulcer is hemorrhage; duodenal ulcer; gastritis; hyperchlorhydria or the functional gastropathy relevant) with medicine; these diseases can or stress situation cause by for example microorganism (for example helicobacter pylori), bacteriotoxin, medicine (for example some anti-inflammatory agent and antirheumatic, for example NSAID and COx-inhibitor), chemical substance (for example ethanol), gastric acid.Should be appreciated that according to common knowledge " gastrointestinal protection " comprises gastroesophageal reflux disease (GERD), its symptom includes but not limited to heartburn and/or sour regurgitation.

In measuring the various models that suppress ulcer and secretion inhibitor characteristic, confirm that The compounds of this invention all significantly is being better than the prior art compound known aspect its various excellent specific properties.Because these characteristics, formula 1 chemical compound and officinal salt thereof are highly suitable for the humans and animals medication, are particularly suitable for they are used for the treatment of and/or when preventing the disease of stomach and/or intestinal.

Therefore, another aspect of the present invention is formula of the present invention 1 chemical compound that is used for the treatment of and/or prevents above-mentioned disease.

Another aspect of the present invention is formula of the present invention 1 chemical compound that is used for the treatment of and/or prevents the formula that is substantially free of 2 chemical compounds of above-mentioned disease.

Formula of the present invention 1 chemical compound that the present invention comprises the formula of being substantially free of 2 chemical compounds equally is used for the treatment of and/or prevents application in the medicine of above-mentioned disease in preparation.

The present invention also comprises the application of formula 1 chemical compound of the present invention in treating and/or preventing above-mentioned disease.

The present invention also comprises the application of formula of the present invention 1 chemical compound in treating and/or preventing above-mentioned disease of the formula of being substantially free of 2 chemical compounds.

Another aspect of the invention is the medicine that comprises one or more formula 1 chemical compounds and/or its officinal salt.

Another aspect of the invention is the medicine that comprises one or more formula 1 chemical compounds and/or its officinal salt, described medicine is substantially free of formula 2 chemical compounds.

These medicines can be prepared by known method own and the well-known method of those skilled in the art.As medicine, pharmacologically active chemical compounds of the present invention (=reactive compound) can itself use, perhaps use with the form of tablet, coated tablet, capsule, suppository, patch (for example as TTS), Emulsion, suspension or solution with suitable pharmaceutical excipient or carrier, reactive compound content is preferably 0.1-95%, can obtain just in time to be suitable for the medicinal form of administration (for example sustained release forms or enteric dosage form) of the persistent period of the required startup of reactive compound and/or effect and/or effect by suitable selection excipient and carrier.

Those skilled in the art are well-known based on his/her Professional knowledge to excipient or the carrier that is applicable to described pharmaceutical formulation.Outside desolventizing, gel former, suppository base, tablet adjuvant and other active compound excipients can also be used, for example antioxidant, dispersant, emulsifying agent, defoamer, correctives, antiseptic, cosolvent, coloring agent or particularly penetration enhancer and complexing agent (for example cyclodextrin) can be used.

Described reactive compound can be taken orally, parenteral or percutaneous dosing.

Usually, verifiedly preferably described reactive compound is given with following dosage when the people is carried out oral administration: daily dose serves as that about 0.01-is about 20, preferred 0.05-5,0.1-1.5mg/kg body weight particularly, if suitably, can multiple dosing, 1-4 administration of preferred branch is to reach required effect.When parenteral is treated, can use similar dosage or (particularly giving under the situation of described reactive compound) to use low dosage usually at intravenous.Any those skilled in the art can both be easily determine the optimal dose and the administering mode of described reactive compound required under the various situations on the basis of his Professional knowledge.

If The compounds of this invention and/or its salt are used for the treatment of above-mentioned disease, then this pharmaceutical formulation also can comprise one or more pharmacologically active principles of other medicines group.If tranquilizer (for example benzodiazepine derivatives medicine, diazepam), spasmolytic (for example bietamiverine or acamylophenine), anticholinergic (for example oxyphencyclimine or phencarbamide), local anesthetic (for example tetracaine or procaine) are arranged the example and suitably enzyme, vitamin or aminoacid.

That Special attention will be given to is The compounds of this invention and the medicine with sour secretion inhibition for example H2 receptor blocking agent (for example cimetidine, ranitidine), H in this manual ⁺/ K ⁺The combination of ATPase inhibitor (for example omeprazole, pantoprazole), perhaps on stack or super stack meaning, increase main render a service and/or eliminate or reduce side effect also with so-called periphery anticholinergic (for example pirenzepine, telenzepine) and with the medication of gastrin antagonist combination, perhaps for control helicobacter pylori further with antibacterial substance (for example cephalosporins, Tetracyclines, penicillins, Macrolide, nitro glyoxaline or bismuth salt) drug combination.The example of suitable antibiotic shared component has mezlocillin, ampicillin, amoxicillin, cefalotin (cefalothin), cefoxitin, cefotaxime, imipenum, gentamycin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and combination (for example clarithromycin+metronidazole) thereof.

Because its good harmonization of the stomach intestinal protective effect, formula 1 chemical compound is suitable for known to have some medicines that cause ulcer function (for example some antiinflammatories and antirheumatic for example NSAID) free or unite use regularly.In addition, formula 1 chemical compound is suitable for regulating the medicine freedom or uniting use regularly with motility.

The pharmacology

The good stomach protective effect and the gastric acid secretion inhibition of chemical compound of the present invention can be confirmed in the research of animal test model.Be provided at its optical antimer shown in formula of the present invention 1 chemical compound studied in the following model and the formula 2, its digital number and alphabetical sequence number are corresponding to these chemical compounds digital number and alphabetical sequence number in an embodiment.

Test is for the secretoinhibitory of perfusion rat stomach

In following table A, shown to give the influence of its optical antimer shown in formula 1 chemical compound of the present invention and the formula 2 in the duodenum to the gastric acid secretion of the perfusion rat stomach of pentagastrin stimulation.

Table A

Digital number	Dosage (μ mol/kg) i.d.	Gastric acid inhibitory secretion (%)	The letter sequence number	Dosage (μ mol/kg) i.d.	Gastric acid inhibitory secretion (%)
Digital number	Dosage (μ mol/kg) i.d.	Gastric acid inhibitory secretion (%)	The letter sequence number	Dosage (μ mol/kg) i.d.	Gastric acid inhibitory secretion (%)	1	1	100	A	3	＜40
2	1	100	B	3	＜40	1	1	100	A	3	＜40
2	1	100	B	3	＜40	3	6	＞50	C	6	＜30
4	3	＞60	D	3	＜40	3	6	＞50	C	6	＜30
4	3	＞60	D	3	＜40	5	3	＞70	E	3	＜30
6	3	100	F	3	＜40	5	3	＞70	E	3	＜30
6	3	100	F	3	＜40	7	1	100	G	3	＜40
8	2	100	H	3	＜40	7	1	100	G	3	＜40
8	2	100	H	3	＜40	9	1	100	I	1	＜50
10	1	100	J	3	＜50	9	1	100	I	1	＜50
10	1	100	J	3	＜50	11	1	100	K	1	＜40
12	3	100				11	1	100	K	1	＜40
12	3	100				13	3	100

Method

At the tracheotomy postoperative, by the epigastrium otch of center open anesthetized rat (the CD rat, female, 200-250g; 1.5g/kg the i.m. urethane) abdominal part and a PVC conduit per os is fixed in the esophagus and another one PVC conduit by pylorus so that the end of this pipe just is projected in the gastral cavity.The conduit of deriving from pylorus is outside the side opening lead body of right stomach wall.

Behind cleaning down (approximately 50-100ml), the physiology NaCl solution that makes warm (37 ℃) continuously by stomach (0.5ml/ minute, pH 6.8-6.9; Braun-Unita I).Measure in each case pH in the effluent of collecting with 15 minutes interval (pH meter 632, glass electrode EA 147; Φ=5mm Metrohm) and by being titrated to pH 7 (Dosimat 665Metrohm) with freshly prepd 0.01N NaOH solution measures excretory HCl.

Finish about 30 minutes of back (after promptly measuring 2 initial flow points) in operation, (=1.65ml/h) pentapeptide Gastrin (left femoral vein) stimulates stomachial secretion by intravenous continuous infusion 1 μ g/kg.Began back 60 minutes at the pentagastrin infusion, with test substance to give in the 2.5ml/kg liquid volume duodenum.Remain at constant 37.8-38 ℃ by infrared ray radiation and heating cushion (automatically, continuous (stepless) of the temperature sensor by a rectum controlled) body temperature animal.

Claims

1. formula 1 chemical compound and salt thereof:

Wherein

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl,

Perhaps wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

Wherein

Aryl is the phenyl of phenyl or replacement, and the phenyl of described replacement has 1,2 or 3 and identical or different is selected from following substituent group: 1-4C-alkyl, 1-4C-alkoxyl, carboxyl, 1-4C-alkoxy carbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano group.

2. formula 1 chemical compound and the salt thereof of claim 1, wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

Wherein

R32 is hydrogen, 1-7C-alkyl, hydroxyl-1-4C-alkyl or 1-4C-alkoxyl-1-4C-alkyl,

Perhaps wherein

Wherein

R6 is hydrogen, 1-4C-alkyl or halogen, and

R7 is hydrogen, 1-4C-alkyl or halogen,

Wherein

3. formula 1 chemical compound and the salt thereof of claim 1, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen, hydroxyl-1-4C-alkyl or 2-4C-alkenyl,

Wherein

R31 is hydrogen, 1-7C-alkyl,

R32 is hydrogen, 1-7C-alkyl,

Perhaps wherein

Wherein

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl, halogen or hydroxyl.

4. formula 1 chemical compound and the salt thereof of claim 1, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen, hydroxyl-1-4C-alkyl or 2-4C-alkenyl,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

Wherein

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl, halogen or hydroxyl.

5. formula 1 chemical compound and the salt thereof of claim 1, wherein

R1 is the 1-4C-alkyl,

R2 is 1-4C-alkyl, halogen or hydroxyl-1-4C-alkyl,

R3 is 1-4C-alkoxyl-1-2C-alkyl or group-CO-NR31R32, wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Perhaps wherein

R31 is pyrrolidino with R32 with the nitrogen-atoms that they were connected,

Phenyl or thienyl that Arom is replaced by R4,

Wherein

R4 is hydrogen, 1-4C-alkyl or halogen.

6. formula 1 chemical compound and the salt thereof of claim 1, wherein

R1 is the 1-4C-alkyl,

R2 is the 1-4C-alkyl,

R3 is group-CO-NR31R32,

Wherein

R31 is hydrogen or 1-7C-alkyl,

R32 is hydrogen or 1-7C-alkyl,

Arom is a phenyl.

7. chemical compound (9S)-2,3-dimethyl-9-phenyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide and salt thereof also.

8. chemical compound (9S)-2,3-dimethyl-9-(2-aminomethyl phenyl)-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide and salt thereof also.

9. chemical compound (9S)-9-(4-fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-pyrans be [2,3-c]-imidazo [1,2-a] pyridine-6-formic acid dimethylformamide and salt thereof also.

10. synthesize the method for formula 1 chemical compound as claimed in claim 1, described method comprises

With formula 8 chemical compounds

Wherein R1, R3 and Arom have the implication that provides in claim 1, change into the racemic mixture of its optical antimer shown in formula 1 chemical compound as claimed in claim 1 and the formula 2, wherein R1, R2, R3 and Arom have the implication that provides in claim 1

And

11. the method for synthetic formula 1 chemical compound as claimed in claim 1, described method comprises

Wherein R1, R2, R3 and Arom have the implication that provides in claim 1,

12. the method for synthetic formula 1 chemical compound as claimed in claim 1, described method comprises

Wherein R1, R2, R3 and Arom have the implication that provides in claim 1,

13. the method for synthetic formula 1 chemical compound as claimed in claim 1, described method comprises

-will be wherein formula 13 chemical compounds with the implication that in claim 1, provides of R1, R2 and R3 change into wherein R1, R2, R3 and Arom have the implication that provides in claim 1 formula 14 chemical compounds

-and formula 14 chemical compounds are further transformed the racemic mixture of its optical antimer shown in an accepted way of doing sth 1 chemical compound and the formula 2

And

14. comprise the chemical compound of claim 1 and/or the medicine of its officinal salt and conventional medicinal adjuvant and/or excipient.

15. comprise the chemical compound of claim 1 and/or the medicine of its officinal salt and conventional medicinal adjuvant and/or excipient, wherein said medicine is substantially free of formula 2 chemical compounds

Wherein R1, R2, R3 and Arom have the implication that provides in claim 1.

16. the chemical compound of claim 1 and officinal salt thereof the application in prevention and treatment disorder of gastrointestinal tract.